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{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc}}
{{other uses|Lyn (disambiguation)}}
{{other uses|Lyn (disambiguation)}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Tyrosine-protein kinase Lyn''' is a [[protein]] that in humans is encoded in humans by the ''LYN'' [[gene]].<ref name="pmid3561390">{{cite journal | vauthors = Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K | title = The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck | journal = Molecular and Cellular Biology | volume = 7 | issue = 1 | pages = 237–43 | date = Jan 1987 | pmid = 3561390 | pmc = 365062 | doi = }}</ref>
'''Tyrosine-protein kinase Lyn''' is a [[protein]] that in humans is encoded by the ''LYN'' [[gene]].<ref name="pmid3561390">{{cite journal | vauthors = Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K | title = The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck | journal = Molecular and Cellular Biology | volume = 7 | issue = 1 | pages = 237–43 | date = Jan 1987 | pmid = 3561390 | pmc = 365062 | doi = 10.1128/MCB.7.1.237}}</ref>


Lyn is a member of the Src family of protein [[tyrosine kinase]]s, which is mainly expressed in [[Haematopoiesis|hematopoietic cells]],<ref>{{cite journal | vauthors = Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K | title = Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 17 | pages = 6538–42 | date = Sep 1989 | pmid = 2505253 | pmc = 297879 | doi = 10.1073/pnas.86.17.6538 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2505253 }}</ref> in neural tissues<ref>{{cite journal | vauthors = Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T | title = Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system | journal = Brain Research. Molecular Brain Research | volume = 16 | issue = 3-4 | pages = 303–10 | date = Dec 1992 | pmid = 1337939 | doi = 10.1016/0169-328X(92)90239-8 }}</ref> liver, and adipose tissue.<ref>{{cite journal | vauthors = Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC | title = Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1 | journal = Cell Metabolism | volume = 11 | issue = 2 | pages = 113–124 | date = Feb 2010 | pmid = 20142099 | pmc = 2830006 | doi = 10.1016/j.cmet.2009.12.010 }}</ref> In various hematopoietic cells, Lyn has emerged as a key [[enzyme]] involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the [[B cell receptor|B cell antigen receptor]] (BCR),<ref>{{cite journal | vauthors = Yamamoto T, Yamanashi Y, Toyoshima K | title = Association of Src-family kinase Lyn with B-cell antigen receptor | journal = Immunological Reviews | volume = 132 | issue = | pages = 187–206 | date = Apr 1993 | pmid = 8349296 | doi = 10.1111/j.1600-065X.1993.tb00843.x }}</ref><ref>{{cite journal | vauthors = Campbell MA, Sefton BM | title = Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases | journal = Molecular and Cellular Biology | volume = 12 | issue = 5 | pages = 2315–21 | date = May 1992 | pmid = 1569953 | pmc = 364403 | doi = | url = http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=1569953 }}</ref> [[CD40]],<ref>{{cite journal | vauthors = Ren CL, Morio T, Fu SM, Geha RS | title = Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2 | journal = The Journal of Experimental Medicine | volume = 179 | issue = 2 | pages = 673–80 | date = Feb 1994 | pmid = 7507510 | pmc = 2191357 | doi = 10.1084/jem.179.2.673 }}</ref> or [[CD19]].<ref name=Campbell>Campbell 1999</ref> The abbreviation '''Lyn''' is derived from '''L'''ck/'''Y'''es '''n'''ovel tyrosine kinase, Lck and Yes also being members of the Src kinase family.
Lyn is a member of the Src family of protein [[tyrosine kinase]]s, which is mainly expressed in [[Haematopoiesis|hematopoietic cells]],<ref>{{cite journal | vauthors = Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K | title = Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 17 | pages = 6538–42 | date = Sep 1989 | pmid = 2505253 | pmc = 297879 | doi = 10.1073/pnas.86.17.6538 | bibcode = 1989PNAS...86.6538Y | doi-access = free }}</ref> in neural tissues<ref>{{cite journal | vauthors = Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T | title = Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system | journal = Brain Research. Molecular Brain Research | volume = 16 | issue = 3–4 | pages = 303–10 | date = Dec 1992 | pmid = 1337939 | doi = 10.1016/0169-328X(92)90239-8 }}</ref> liver, and adipose tissue.<ref>{{cite journal | vauthors = Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC | title = Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1 | journal = Cell Metabolism | volume = 11 | issue = 2 | pages = 113–124 | date = Feb 2010 | pmid = 20142099 | pmc = 2830006 | doi = 10.1016/j.cmet.2009.12.010 }}</ref> In various hematopoietic cells, Lyn has emerged as a key [[enzyme]] involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the [[B cell receptor|B cell antigen receptor]] (BCR),<ref>{{cite journal | vauthors = Yamamoto T, Yamanashi Y, Toyoshima K | title = Association of Src-family kinase Lyn with B-cell antigen receptor | journal = Immunological Reviews | volume = 132 | pages = 187–206 | date = Apr 1993 | pmid = 8349296 | doi = 10.1111/j.1600-065X.1993.tb00843.x | s2cid = 10782326 }}</ref><ref>{{cite journal | vauthors = Campbell MA, Sefton BM | title = Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases | journal = Molecular and Cellular Biology | volume = 12 | issue = 5 | pages = 2315–21 | date = May 1992 | pmid = 1569953 | pmc = 364403 | doi = 10.1128/MCB.12.5.2315}}</ref> [[CD40]],<ref>{{cite journal | vauthors = Ren CL, Morio T, Fu SM, Geha RS | title = Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2 | journal = The Journal of Experimental Medicine | volume = 179 | issue = 2 | pages = 673–80 | date = Feb 1994 | pmid = 7507510 | pmc = 2191357 | doi = 10.1084/jem.179.2.673 }}</ref> or [[CD19]].<ref name=Campbell>Campbell 1999</ref> The abbreviation '''Lyn''' is derived from '''L'''ck/'''Y'''es '''n'''ovel tyrosine kinase, Lck and Yes also being members of the Src kinase family.


== Function ==
== Function ==


Lyn has been described to have an inhibitory role in [[myeloid]] lineage proliferation.<ref name="Harder2001">{{cite journal | vauthors = Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML | title = Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage | journal = Immunity | volume = 15 | issue = 4 | pages = 603–615 | date = Oct 2001 | pmid = 11672542 | doi = 10.1016/S1074-7613(01)00208-4 }}</ref> Following engagement of the B cell receptors, Lyn undergoes rapid [[phosphorylation]] and activation. LYN activation triggers a [[signal transduction|cascade of signaling event]]s mediated by Lyn phosphorylation of tyrosine residues within the [[immunoreceptor tyrosine-based activation motif]]s (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including [[Syk]], [[PLCG2|phosholipase Cγ2]] (PLCγ2) and [[Phosphoinositide 3-kinase|phosphatidyl inositol-3 kinase]].<ref name=Campbell /><ref>{{cite journal | vauthors = Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, Yamamoto T | title = Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 3 | pages = 1118–22 | date = Feb 1992 | pmid = 1371009 | pmc = 48397 | doi = 10.1073/pnas.89.3.1118 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1371009 }}</ref> These kinases provide activation signals, which play critical roles in proliferation, Ca<sup>2+</sup> mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the [[immunoreceptor tyrosine-based inhibitory motif]]s (ITIM) in regulatory proteins such as [[CD22]], PIR-B and [[FCGR2B|FCγRIIb1]]. Their ITIM phosphorylation subsequently leads to recruitment and activation of [[phosphatase]]s such as [[INPP5D|SHIP-1]] and [[PTPN6|SHP-1]],<ref>{{cite journal | vauthors = Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC | title = Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection | journal = Immunity | volume = 8 | issue = 4 | pages = 497–508 | date = Apr 1998 | pmid = 9586639 | doi = 10.1016/S1074-7613(00)80554-3 | url = http://linkinghub.elsevier.com/retrieve/pii/S1074-7613(00)80554-3 }}</ref><ref>{{cite journal | vauthors = Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT | title = Inhibition of the B cell by CD22: a requirement for Lyn | journal = The Journal of Experimental Medicine | volume = 187 | issue = 5 | pages = 807–11 | date = Mar 1998 | pmid = 9480991 | pmc = 2212179 | doi = 10.1084/jem.187.5.807 | url = http://www.jem.org/cgi/pmidlookup?view=long&pmid=9480991 }}</ref><ref name="pmid9601638">{{cite journal | vauthors = Chan VW, Lowell CA, DeFranco AL | title = Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes | journal = Current Biology | volume = 8 | issue = 10 | pages = 545–53 | date = May 1998 | pmid = 9601638 | doi = 10.1016/S0960-9822(98)70223-4 | url = http://linkinghub.elsevier.com/retrieve/pii/S0960-9822(98)70223-4 }}</ref><ref name="pmid9547345">{{cite journal | vauthors = Nishizumi H, Horikawa K, Mlinaric-Rascan I, Yamamoto T | title = A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals | journal = The Journal of Experimental Medicine | volume = 187 | issue = 8 | pages = 1343–8 | date = Apr 1998 | pmid = 9547345 | pmc = 2212230 | doi = 10.1084/jem.187.8.1343 | url = http://www.jem.org/cgi/pmidlookup?view=long&pmid=9547345 }}</ref><ref name="pmid10327049">{{cite journal | vauthors = Maeda A, Scharenberg AM, Tsukada S, Bolen JB, Kinet JP, Kurosaki T | title = Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1 | journal = Oncogene | volume = 18 | issue = 14 | pages = 2291–7 | date = Apr 1999 | pmid = 10327049 | doi = 10.1038/sj.onc.1202552 }}</ref> which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In [[B cell]]s, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.<ref name="pmid15220000">{{cite journal | vauthors = Lowell CA | title = Src-family kinases: rheostats of immune cell signaling | journal = Molecular Immunology | volume = 41 | issue = 6-7 | pages = 631–43 | date = Jul 2004 | pmid = 15220000 | doi = 10.1016/j.molimm.2004.04.010 }}</ref><ref name="pmid12563261">{{cite journal | vauthors = Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A | title = Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development | journal = Nature Immunology | volume = 4 | issue = 3 | pages = 274–9 | date = Mar 2003 | pmid = 12563261 | doi = 10.1038/ni893 }}</ref><ref name="pmid15664155">{{cite journal | vauthors = Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM | title = Lyn tyrosine kinase: accentuating the positive and the negative | journal = Immunity | volume = 22 | issue = 1 | pages = 9–18 | date = Jan 2005 | pmid = 15664155 | doi = 10.1016/j.immuni.2004.12.004 }}</ref>
Lyn has been described to have an inhibitory role in [[myeloid]] lineage proliferation.<ref name="Harder2001">{{cite journal | vauthors = Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML | title = Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage | journal = Immunity | volume = 15 | issue = 4 | pages = 603–615 | date = Oct 2001 | pmid = 11672542 | doi = 10.1016/S1074-7613(01)00208-4 | doi-access = free }}</ref> Following engagement of the B cell receptors, Lyn undergoes rapid [[phosphorylation]] and activation. LYN activation triggers a [[signal transduction|cascade of signaling event]]s mediated by Lyn phosphorylation of tyrosine residues within the [[immunoreceptor tyrosine-based activation motif]]s (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including [[Syk]], [[PLCG2|phosholipase Cγ2]] (PLCγ2) and [[Phosphoinositide 3-kinase|phosphatidyl inositol-3 kinase]].<ref name=Campbell /><ref>{{cite journal | vauthors = Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, Yamamoto T | title = Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 3 | pages = 1118–22 | date = Feb 1992 | pmid = 1371009 | pmc = 48397 | doi = 10.1073/pnas.89.3.1118 | bibcode = 1992PNAS...89.1118Y | doi-access = free }}</ref> These kinases provide activation signals, which play critical roles in proliferation, Ca<sup>2+</sup> mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the [[immunoreceptor tyrosine-based inhibitory motif]]s (ITIM) in regulatory proteins such as [[CD22]], PIR-B and [[FCGR2B|FCγRIIb1]]. Their ITIM phosphorylation subsequently leads to recruitment and activation of [[phosphatase]]s such as [[INPP5D|SHIP-1]] and [[PTPN6|SHP-1]],<ref>{{cite journal | vauthors = Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC | title = Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection | journal = Immunity | volume = 8 | issue = 4 | pages = 497–508 | date = Apr 1998 | pmid = 9586639 | doi = 10.1016/S1074-7613(00)80554-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT | title = Inhibition of the B cell by CD22: a requirement for Lyn | journal = The Journal of Experimental Medicine | volume = 187 | issue = 5 | pages = 807–11 | date = Mar 1998 | pmid = 9480991 | pmc = 2212179 | doi = 10.1084/jem.187.5.807 }}</ref><ref name="pmid9601638">{{cite journal | vauthors = Chan VW, Lowell CA, DeFranco AL | title = Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes | journal = Current Biology | volume = 8 | issue = 10 | pages = 545–53 | date = May 1998 | pmid = 9601638 | doi = 10.1016/S0960-9822(98)70223-4 | s2cid = 12195731 | doi-access = free | bibcode = 1998CBio....8..545C }}</ref><ref name="pmid9547345">{{cite journal | vauthors = Nishizumi H, Horikawa K, Mlinaric-Rascan I, Yamamoto T | title = A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals | journal = The Journal of Experimental Medicine | volume = 187 | issue = 8 | pages = 1343–8 | date = Apr 1998 | pmid = 9547345 | pmc = 2212230 | doi = 10.1084/jem.187.8.1343 }}</ref><ref name="pmid10327049">{{cite journal | vauthors = Maeda A, Scharenberg AM, Tsukada S, Bolen JB, Kinet JP, Kurosaki T | title = Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1 | journal = Oncogene | volume = 18 | issue = 14 | pages = 2291–7 | date = Apr 1999 | pmid = 10327049 | doi = 10.1038/sj.onc.1202552 | doi-access = free }}</ref> which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In [[B cell]]s, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.<ref name="pmid15220000">{{cite journal | vauthors = Lowell CA | title = Src-family kinases: rheostats of immune cell signaling | journal = Molecular Immunology | volume = 41 | issue = 6–7 | pages = 631–43 | date = Jul 2004 | pmid = 15220000 | doi = 10.1016/j.molimm.2004.04.010 }}</ref><ref name="pmid12563261">{{cite journal | vauthors = Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A | title = Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development | journal = Nature Immunology | volume = 4 | issue = 3 | pages = 274–9 | date = Mar 2003 | pmid = 12563261 | doi = 10.1038/ni893 | s2cid = 32559368 }}</ref><ref name="pmid15664155">{{cite journal | vauthors = Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM | title = Lyn tyrosine kinase: accentuating the positive and the negative | journal = Immunity | volume = 22 | issue = 1 | pages = 9–18 | date = Jan 2005 | pmid = 15664155 | doi = 10.1016/j.immuni.2004.12.004 | doi-access = free }}</ref> HSP90 inhibitor NVP-BEP800 has been described to affect stability of LYN kinase and growth of B-cell acute lymphoblastic leukemias through inhibition of the NF-kappaB signaling. <ref name="pmid33737511">{{cite journal |vauthors=Mshaik R, Simonet J, Georgievski A, Jamal L, Bechoua S, Ballerini P, Bellaye PS, Mlamla Z, Pais de Barros JP, Geissler A, Francin PJ, Girodon F, Garrido C, Quéré R | title = HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemia | journal = Blood Cancer J. | volume = 3 | issue = 11 | page = 61 | date = March 2021 | pmid = 33737511 | doi = 10.1038/s41408-021-00450-2 | pmc = 7973815 | doi-access = free }}</ref>

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LYN is reported to be a key signal mediator for estrogen-dependent suppression of human osteoclast differentiation, survival, and function.<ref>{{cite journal |last1=Gavali |first1=Shubhangi |last2=Gupta |first2=Manoj Kumar |last3=Daswani |first3=Bhavna |last4=Wani |first4=Mohan R. |last5=Sirdeshmukh |first5=Ravi |last6=Khatkhatay |first6=M. Ikram |title=LYN, a key mediator in estrogen-dependent suppression of osteoclast differentiation, survival, and function |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |date=March 2019 |volume=1865 |issue=3 |pages=547–557 |doi=10.1016/j.bbadis.2018.12.016 |pmid=30579930 |doi-access=free }}</ref> Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.<ref name="Müller2000a">{{cite journal | vauthors = Müller G, Wied S, Frick W | title = Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4708–4723 | date = Jul 2000 | pmid = 10848597 | pmc = 85892 | doi = 10.1128/mcb.20.13.4708-4723.2000 }}</ref> In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.<ref name="Anderwald 2002">{{cite journal | vauthors = Anderwald C, Müller G, Koca G, Fürnsinn C, Waldhäusl W, Roden M | title = Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2 | journal = Molecular Endocrinology | volume = 16 | issue = 7 | pages = 1612–1628 | date = Jul 2002 | pmid = 12089355 | doi = 10.1210/mend.16.7.0867 | doi-access = free }}</ref>
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The insulin secretagogue, [[Glimepiride|glimepiride (Amaryl®)]] activates Lyn in adipocytes via the disruption of lipid rafts.<ref name="Müller 2000b">{{cite journal | vauthors = Müller G | title = The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl | journal = Molecular Medicine | volume = 6 | issue = 11 | pages = 907–933 | date = Nov 2000 | pmid = 11147570 | pmc = 1949923 | doi = 10.1007/BF03401827}}</ref> This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.<ref name="Müller 2000b" /><ref name="Müller et al 2005">{{cite journal | vauthors = Müller G, Schulz A, Wied S, Frick W | title = Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes | journal = Biochemical Pharmacology | volume = 69 | issue = 5 | pages = 761–780 | date = Mar 2005 | pmid = 15710354 | doi = 10.1016/j.bcp.2004.11.014 }}</ref> [[Tolimidone]] (MLR-1023) is a small molecule allosteric activator of lyn kinase with an EC50 of 63 nM<ref>{{cite journal | vauthors = Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS | title = The Lyn kinase activator MLR-123 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes | journal = J Pharmacol Exp Ther | volume = 342 | issue = 1 | pages = 23–32 | date = 2012 | pmid = 22431203 | doi = 10.1124/jpet.112.192187 | s2cid = 7288053 | url = http://jpet.aspetjournals.org/content/suppl/2012/03/19/jpet.112.192187 }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite journal | vauthors = Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG | title = MLR-1023 is potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 342| issue = 1 | pages = 15–22 | date = 2011 | pmid =22473614| doi = 10.1124/jpet.112.192096 | s2cid = 26419896 | url = http://jpet.aspetjournals.org/content/342/1/15}}</ref> that is currently under Phase 2a investigation for Type II diabetes.<ref>{{cite web|title=Melior Pharmaceuticals Initiates Phase 2 Study with MLR-1023 for Type 2 Diabetes|date=3 March 2015 |url=http://www.businesswire.com/news/home/20150303005277/en/Melior-Pharmaceuticals-Initiates-Phase-2-Study-MLR-1023#.VVy7eGCKKkJ|publisher=Business Wire|access-date=March 3, 2015}}</ref> In June, 2016, the sponsor of these studies, [[Melior Discovery]], announced positive results from their Phase 2a study with tolimidone in diabetic patients,<ref>{{Cite web|url=http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results|title=Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study|website=www.businesswire.com|date=13 June 2016 |language=en|access-date=2017-08-04}}</ref><ref>{{cite journal | vauthors = Lee MK, Kim SG, Watkins E, Moon MK, Rhee SY, Frias JP, Chung CH, Lee SH, Block B, Cha BS, Park HK, Kim BJ, Greenway F | title = A Novel Non-PPARgamma Insulin Sensitizer: MLR-1023 Clinical Proof-of-concept in Type 2 Diabetes Mellitus | journal = J. Diabetes Complications | volume = 34| issue = 5 | pages = 107555 | date = May 2020 | pmid = 32019723| doi = 10.1016/j.jdiacomp.2020.107555 | s2cid = 211036334 | url = https://doi.org/10.1185/030079907X188152 }}</ref> and the continuation of additional clinical studies.<ref>{{Cite web|url=http://www.meliordiscovery.com/media_press.html|title=Melior Discovery website press releases|access-date=2018-06-11|archive-date=2018-05-17|archive-url=https://web.archive.org/web/20180517032422/http://www.meliordiscovery.com/media_press.html|url-status=dead}}</ref>

Lyn has been shown to protect against hepatocellular [[apoptosis]] and promote [[liver regeneration]] through the preservation of hepatocellular mitochondrial integrity.<ref>{{cite journal | vauthors = Gringeri E, Carraro A, Tibaldi E, D'Amico FE, Mancon M, Toninello A, Pagano MA, Vio C, Cillo U, Brunati AM | title = Lyn-mediated mitochondrial tyrosine phosphorylation is required to preserve mitochondrial integrity in early liver regeneration | journal = The Biochemical Journal | volume = 425 | issue = 2 | pages = 401–12 | date = December 2009 | pmid = 19832701 | doi = 10.1042/BJ20090902 | url = https://hal.archives-ouvertes.fr/hal-00479212/file/PEER_stage2_10.1042%252FBJ20090902.pdf }}</ref>

Several investigators have shown the role of lyn kinase in different aspects of pulmonary function. Lyn activation in [[Respiratory epithelium|pulmonary epithelium]] has been shown to be important in improving pulmonary barrier integrity and to reduce [[Pulmonary edema|edema]].<ref>{{cite journal | vauthors = Jan J, Zhang G, Welch EJ, Liang Y, Fu J, Vogel SM, Lowell CA, Du X, Cheresh DA, Malik AB, Li Z | title = A critical role for Lyn kinase in strengthening endothelial integrity and barrier function | journal = Blood | volume = 122| issue = 25 | pages = 4140–4149 | date = Dec 2013 | pmid = 24108461| doi = 10.1182/blood-2013-03-491423 | pmc = 3862279 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Corey SJ, Day RM | title = Shockingly: the loss of Lyn leads to leakiness | journal = Blood | volume = 122| issue = 25 | pages = 4009–4010 | date = Dec 2013 | pmid = 24335031| doi = 10.1182/blood-2013-10-533158| pmc = 3862277 }}</ref> Additional evidence suggest that lyn activation in [[Pulmonary alveolus|alveolar]] phagocytes improves phagocytosis of bacteria and reduces [[Respiratory infection|pulmonary infection]]. <ref>{{cite journal | vauthors = Li X, He S, Zhou X, Ye Y, Tan S, Zhang S, Li R, Yu M, Jundt MC, Hidebrand A, Wang Y, Li G, Huang C, Wu M | title = Lyn delivers bacteria to lysosomes for eradication through TLR2-initiated autophagy related phagocytosis | journal = PLOS Pathogens| volume = 12| issue = 1 | pages = e1005363 | date = Jan 2016 | pmid = 26735693| doi = 10.1371/journal.ppat.1005363 | pmc = 4703367 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li X, Zhou X, Ye Y, Li Y, Li J, Privratsky B, Wu E, Gao H, Huang C, Wu M | title = Lyn regulates inflammatory responses in Klebsiella pneumonia infection via the p38/NF-kB pathway | journal = Eur. J. Immunol. | volume = 44| issue = 3| pages = 763–773 | date = 2012 | pmid = 24338528| doi = 10.1002/eji.201343972 | pmc = 4103995 }}</ref> Finally, other research has found that lyn activation reduces pulmonary hypersecretion of mucus. <ref>{{cite journal | vauthors = Wang X, Li Y, Wang X, Zhang Y, Liu Z, Zhong N, Wu M, Li G | title = Lyn regulates mucus secretion and MUC5AC via the STAT6 signaling pathway during allergic airway inflammation | journal = Sci Rep | volume = 7| date = Feb 2016 | page = 42675 | pmid = 28205598| doi = 10.1038/srep42675 | pmc = 5312001 | doi-access = free}}</ref>


⚫
Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.<ref name="Müller2000a">{{cite journal | vauthors = Müller G, Wied S, Frick W | title = Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4708–4723 | date = Jul 2000 | pmid = 10848597 | pmc = 85892 | doi = 10.1128/mcb.20.13.4708-4723.2000 }}</ref> In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.<ref name="Anderwald 2002">{{cite journal | vauthors = Anderwald C, Müller G, Koca G, Fürnsinn C, Waldhäusl W, Roden M | title = Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2 | journal = Molecular Endocrinology | volume = 16 | issue = 7 | pages = 1612–1628 | date = Jul 2002 | pmid = 12089355 | pmc = | doi = 10.1210/me.16.7.1612 }}</ref>
⚫
The insulin secretagogue, [[Glimepiride|glimepiride (Amaryl®)]] activates Lyn in adipocytes via the disruption of lipid rafts.<ref name="Müller 2000b">{{cite journal | vauthors = Müller G | title = The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl | journal = Molecular Medicine | volume = 6 | issue = 11 | pages = 907–933 | date = Nov 2000 | pmid = 11147570 | pmc = 1949923 | doi = }}</ref> This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.<ref name="Müller 2000b" /><ref name="Müller et al 2005">{{cite journal | vauthors = Müller G, Schulz A, Wied S, Frick W | title = Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes | journal = Biochemical Pharmacology | volume = 69 | issue = 5 | pages = 761–780 | date = Mar 2005 | pmid = 15710354 | doi = 10.1016/j.bcp.2004.11.014 }}</ref> [[Tolimidone]] is a small molecule lyn activator that is currently under Phase 2a investigation for Type II diabetes.<ref>{{cite web|title=Melior Pharmaceuticals Initiates Phase 2 Study with MLR-1023 for Type 2 Diabetes|url=http://www.businesswire.com/news/home/20150303005277/en/Melior-Pharmaceuticals-Initiates-Phase-2-Study-MLR-1023#.VVy7eGCKKkJ|publisher=Business Wire|accessdate=March 3, 2015}}</ref> In June, 2016, the sponsor of these studies, [[Melior Discovery]] announced positive results from their Phase 2a study with tolimidone in diabetic patients<ref>{{Cite web|url=http://www.businesswire.com/news/home/20160613005028/en/Melior-Pharmaceuticals-Announces-Positive-Phase-2A-Results|title=Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study|website=www.businesswire.com|language=en|access-date=2017-08-04}}</ref>.


== Pathology ==
== Pathology ==
Line 16: Line 23:
Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and monocyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells.<ref name="Harder2001" />
Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and monocyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells.<ref name="Harder2001" />


Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.<ref name="pmid12486102">{{cite journal | vauthors = Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C, Casagranda F, Dunn AR, Tarlinton DM | title = Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity | journal = The Journal of Experimental Medicine | volume = 196 | issue = 12 | pages = 1593–604 | date = Dec 2002 | pmid = 12486102 | pmc = 2196073 | doi = 10.1084/jem.20020515 | url = http://www.jem.org/cgi/pmidlookup?view=long&pmid=12486102 }}</ref>
Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.<ref name="pmid12486102">{{cite journal | vauthors = Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C, Casagranda F, Dunn AR, Tarlinton DM | title = Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity | journal = The Journal of Experimental Medicine | volume = 196 | issue = 12 | pages = 1593–604 | date = Dec 2002 | pmid = 12486102 | pmc = 2196073 | doi = 10.1084/jem.20020515 }}</ref>


== Interactions ==
== Interactions ==
LYN has been shown to [[Protein-protein interaction|interact]] with:
LYN has been shown to [[Protein-protein interaction|interact]] with:

c-Kit,<ref>{{Cite journal|last=Linnekin|first=Diana|last2=DeBerry|first2=Candy S.|last3=Mou|first3=Sherry|date=1997-10-24|title=Lyn Associates with the Juxtamembrane Region of c-Kit and Is Activated by Stem Cell Factor in Hematopoietic Cell Lines and Normal Progenitor Cells|url=http://www.jbc.org/content/272/43/27450|journal=Journal of Biological Chemistry|language=en|volume=272|issue=43|pages=27450–27455|doi=10.1074/jbc.272.43.27450|issn=0021-9258|pmid=9341198}}</ref>
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[BCAR1]],<ref name = pmid9020138>{{cite journal | vauthors = Manié SN, Beck AR, Astier A, Law SF, Canty T, Hirai H, Druker BJ, Avraham H, Haghayeghi N, Sattler M, Salgia R, Griffin JD, Golemis EA, Freedman AS | title = Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4230–6 | date = Feb 1997 | pmid = 9020138 | doi = 10.1074/jbc.272.7.4230 }}</ref><ref name = pmid9581808>{{cite journal | vauthors = Qiu W, Cobb RR, Scholz W | title = Inhibition of p130cas tyrosine phosphorylation by calyculin A | journal = Journal of Leukocyte Biology | volume = 63 | issue = 5 | pages = 631–5 | date = May 1998 | pmid = 9581808 | doi = }}</ref>
* [[BCAR1]],<ref name = pmid9020138>{{cite journal | vauthors = Manié SN, Beck AR, Astier A, Law SF, Canty T, Hirai H, Druker BJ, Avraham H, Haghayeghi N, Sattler M, Salgia R, Griffin JD, Golemis EA, Freedman AS | title = Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 7 | pages = 4230–6 | date = Feb 1997 | pmid = 9020138 | doi = 10.1074/jbc.272.7.4230 | doi-access = free | hdl = 20.500.12613/9177 | hdl-access = free }}</ref><ref name = pmid9581808>{{cite journal | vauthors = Qiu W, Cobb RR, Scholz W | title = Inhibition of p130cas tyrosine phosphorylation by calyculin A | journal = Journal of Leukocyte Biology | volume = 63 | issue = 5 | pages = 631–5 | date = May 1998 | pmid = 9581808 | doi = 10.1002/jlb.63.5.631| s2cid = 11177730 | doi-access = free }}</ref>
* [[CD117]],<ref name = pmid11825908>{{cite journal | vauthors = Liang X, Wisniewski D, Strife A, Clarkson B, Resh MD | title = Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 13732–8 | date = Apr 2002 | pmid = 11825908 | doi = 10.1074/jbc.M200277200 }}</ref><ref name = pmid9341198>{{cite journal | vauthors = Linnekin D, DeBerry CS, Mou S | title = Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 43 | pages = 27450–5 | date = Oct 1997 | pmid = 9341198 | doi = 10.1074/jbc.272.43.27450 }}</ref>
* [[CD117]],<ref name = pmid11825908>{{cite journal | vauthors = Liang X, Wisniewski D, Strife A, Clarkson B, Resh MD | title = Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 16 | pages = 13732–8 | date = Apr 2002 | pmid = 11825908 | doi = 10.1074/jbc.M200277200 | doi-access = free }}</ref><ref name = pmid9341198>{{cite journal | vauthors = Linnekin D, DeBerry CS, Mou S | title = Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 43 | pages = 27450–5 | date = Oct 1997 | pmid = 9341198 | doi = 10.1074/jbc.272.43.27450 | doi-access = free }}</ref>
* [[CD22]],<ref name = pmid10748054>{{cite journal | vauthors = Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF | title = CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux | journal = The Journal of Biological Chemistry | volume = 275 | issue = 23 | pages = 17420–7 | date = Jun 2000 | pmid = 10748054 | doi = 10.1074/jbc.M001892200 }}</ref><ref name = pmid10228003>{{cite journal | vauthors = Greer SF, Justement LB | title = CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1 | journal = Journal of Immunology | volume = 162 | issue = 9 | pages = 5278–86 | date = May 1999 | pmid = 10228003 | doi = }}</ref>
* [[CD22]],<ref name = pmid10748054>{{cite journal | vauthors = Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF | title = CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux | journal = The Journal of Biological Chemistry | volume = 275 | issue = 23 | pages = 17420–7 | date = Jun 2000 | pmid = 10748054 | doi = 10.1074/jbc.M001892200 | doi-access = free }}</ref><ref name = pmid10228003>{{cite journal | vauthors = Greer SF, Justement LB | title = CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1 | journal = Journal of Immunology | volume = 162 | issue = 9 | pages = 5278–86 | date = May 1999 | doi = 10.4049/jimmunol.162.9.5278 | pmid = 10228003 | doi-access = free }}</ref>
* [[Cdk1]],<ref name = pmid8051175>{{cite journal | vauthors = Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D | title = Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation | journal = The Journal of Biological Chemistry | volume = 269 | issue = 32 | pages = 20739–43 | date = Aug 1994 | pmid = 8051175 | doi = }}</ref><ref name = pmid8910336>{{cite journal | vauthors = Pathan NI, Geahlen RL, Harrison ML | title = The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27517–23 | date = Nov 1996 | pmid = 8910336 | doi = 10.1074/jbc.271.44.27517 }}</ref>
* [[Cdk1]],<ref name = pmid8051175>{{cite journal | vauthors = Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D | title = Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation | journal = The Journal of Biological Chemistry | volume = 269 | issue = 32 | pages = 20739–43 | date = Aug 1994 | doi = 10.1016/S0021-9258(17)32054-9 | pmid = 8051175 | doi-access = free }}</ref><ref name = pmid8910336>{{cite journal | vauthors = Pathan NI, Geahlen RL, Harrison ML | title = The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27517–23 | date = Nov 1996 | pmid = 8910336 | doi = 10.1074/jbc.271.44.27517 | doi-access = free }}</ref>
* [[DOK1]],<ref name = pmid11825908/><ref name = pmid11071635>{{cite journal | vauthors = van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M | title = Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells | journal = Blood | volume = 96 | issue = 10 | pages = 3406–13 | date = Nov 2000 | pmid = 11071635 | doi = }}</ref>
* [[DOK1]],<ref name = pmid11825908/><ref name = pmid11071635>{{cite journal | vauthors = van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M | title = Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells | journal = Blood | volume = 96 | issue = 10 | pages = 3406–13 | date = Nov 2000 | pmid = 11071635 | doi = 10.1182/blood.V96.10.3406| url = https://pure.eur.nl/en/publications/395fb5fc-60e3-45d7-a9b1-fc7b9cc6b4bc | hdl = 1765/9530 | hdl-access = free }}</ref>
* [[Erythropoietin receptor|EPOR]]<ref name = pmid9573010>{{cite journal | vauthors = Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O | title = Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway | journal = Blood | volume = 91 | issue = 10 | pages = 3734–45 | date = May 1998 | pmid = 9573010 | doi = }}</ref>
* [[Erythropoietin receptor|EPOR]]<ref name = pmid9573010>{{cite journal | vauthors = Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O | title = Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway | journal = Blood | volume = 91 | issue = 10 | pages = 3734–45 | date = May 1998 | pmid = 9573010 | doi = 10.1182/blood.V91.10.3734| doi-access = free }}</ref>
* [[GPVI]],<ref name = pmid11943772>{{cite journal | vauthors = Suzuki-Inoue K, Tulasne D, Shen Y, Bori-Sanz T, Inoue O, Jung SM, Moroi M, Andrews RK, Berndt MC, Watson SP | title = Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 24 | pages = 21561–6 | date = Jun 2002 | pmid = 11943772 | doi = 10.1074/jbc.M201012200 }}</ref>
* [[GPVI]],<ref name = pmid11943772>{{cite journal | vauthors = Suzuki-Inoue K, Tulasne D, Shen Y, Bori-Sanz T, Inoue O, Jung SM, Moroi M, Andrews RK, Berndt MC, Watson SP | title = Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling | journal = The Journal of Biological Chemistry | volume = 277 | issue = 24 | pages = 21561–6 | date = Jun 2002 | pmid = 11943772 | doi = 10.1074/jbc.M201012200 | doi-access = free }}</ref>
* [[INPP5D]],<ref name = pmid12882960>{{cite journal | vauthors = Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB | title = The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 40 | pages = 38628–36 | date = Oct 2003 | pmid = 12882960 | doi = 10.1074/jbc.M305021200 }}</ref>
* [[INPP5D]],<ref name = pmid12882960>{{cite journal | vauthors = Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB | title = The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 40 | pages = 38628–36 | date = Oct 2003 | pmid = 12882960 | doi = 10.1074/jbc.M305021200 | doi-access = free }}</ref>
* [[IRS1]],<ref name = "Muller2000">{{cite journal | vauthors = Müller G, Wied S, Frick W | title = Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4708–23 | date = Jul 2000 | pmid = 10848597 | pmc = 85892 | doi = 10.1128/mcb.20.13.4708-4723.2000 }}</ref>
* [[IRS1]],<ref name = "Muller2000">{{cite journal | vauthors = Müller G, Wied S, Frick W | title = Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4708–23 | date = Jul 2000 | pmid = 10848597 | pmc = 85892 | doi = 10.1128/mcb.20.13.4708-4723.2000 }}</ref>
* [[Lymphocyte cytosolic protein 2|LCP2]],<ref name = pmid10026222>{{cite journal | vauthors = Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, Koretzky GA, Watson SP | title = Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets | journal = The Journal of Biological Chemistry | volume = 274 | issue = 9 | pages = 5963–71 | date = Feb 1999 | pmid = 10026222 | doi = 10.1074/jbc.274.9.5963 }}</ref>
* [[Lymphocyte cytosolic protein 2|LCP2]],<ref name = pmid10026222>{{cite journal | vauthors = Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, Koretzky GA, Watson SP | title = Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets | journal = The Journal of Biological Chemistry | volume = 274 | issue = 9 | pages = 5963–71 | date = Feb 1999 | pmid = 10026222 | doi = 10.1074/jbc.274.9.5963 | doi-access = free }}</ref>
* [[MUC1]],<ref name="pmid12750562">{{cite journal | vauthors = Durum SK, Aiello FB | title = Interleukin-7 induces MUC1 | journal = Cancer Biology & Therapy | volume = 2 | issue = 2 | pages = 194–5 | year = 2003 | pmid = 12750562 | doi = 10.4161/cbt.2.2.351 }}</ref>
* [[MUC1]],<ref name="pmid12750562">{{cite journal | vauthors = Durum SK, Aiello FB | title = Interleukin-7 induces MUC1 | journal = Cancer Biology & Therapy | volume = 2 | issue = 2 | pages = 194–5 | year = 2003 | pmid = 12750562 | doi = 10.4161/cbt.2.2.351 | doi-access = free }}</ref>
* [[NEDD9]],<ref name = pmid9020138/>
* [[NEDD9]],<ref name = pmid9020138/>
* [[PLCG2]],<ref name = pmid8395016>{{cite journal | vauthors = Pleiman CM, Clark MR, Gauen LK, Winitz S, Coggeshall KM, Johnson GL, Shaw AS, Cambier JC | title = Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p56lyn which interact with the effector molecules phospholipase C-gamma 2, microtubule-associated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase | journal = Molecular and Cellular Biology | volume = 13 | issue = 9 | pages = 5877–87 | date = Sep 1993 | pmid = 8395016 | pmc = 360336 | doi = }}</ref><ref name = pmid10981967>{{cite journal | vauthors = Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ | title = Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex | journal = Immunity | volume = 13 | issue = 2 | pages = 243–53 | date = Aug 2000 | pmid = 10981967 | doi = 10.1016/s1074-7613(00)00024-8 }}</ref>
* [[PLCG2]],<ref name = pmid8395016>{{cite journal | vauthors = Pleiman CM, Clark MR, Gauen LK, Winitz S, Coggeshall KM, Johnson GL, Shaw AS, Cambier JC | title = Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p56lyn which interact with the effector molecules phospholipase C-gamma 2, microtubule-associated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase | journal = Molecular and Cellular Biology | volume = 13 | issue = 9 | pages = 5877–87 | date = Sep 1993 | pmid = 8395016 | pmc = 360336 | doi = 10.1128/MCB.13.9.5877}}</ref><ref name = pmid10981967>{{cite journal | vauthors = Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ | title = Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex | journal = Immunity | volume = 13 | issue = 2 | pages = 243–53 | date = Aug 2000 | pmid = 10981967 | doi = 10.1016/s1074-7613(00)00024-8 | doi-access = free }}</ref>
* [[PPP1R15A]],<ref name = pmid11517336>{{cite journal | vauthors = Grishin AV, Azhipa O, Semenov I, Corey SJ | title = Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 18 | pages = 10172–7 | date = Aug 2001 | pmid = 11517336 | pmc = 56934 | doi = 10.1073/pnas.191130798 }}</ref>
* [[PPP1R15A]],<ref name = pmid11517336>{{cite journal | vauthors = Grishin AV, Azhipa O, Semenov I, Corey SJ | title = Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 18 | pages = 10172–7 | date = Aug 2001 | pmid = 11517336 | pmc = 56934 | doi = 10.1073/pnas.191130798 | bibcode = 2001PNAS...9810172G | doi-access = free }}</ref>
* [[PTPRC]],<ref name = pmid7516335>{{cite journal | vauthors = Brown VK, Ogle EW, Burkhardt AL, Rowley RB, Bolen JB, Justement LB | title = Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 25 | pages = 17238–44 | date = Jun 1994 | pmid = 7516335 | doi = }}</ref>
* [[PTPRC]],<ref name = pmid7516335>{{cite journal | vauthors = Brown VK, Ogle EW, Burkhardt AL, Rowley RB, Bolen JB, Justement LB | title = Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 25 | pages = 17238–44 | date = Jun 1994 | doi = 10.1016/S0021-9258(17)32545-0 | pmid = 7516335 | doi-access = free }}</ref>
* [[Syk]],<ref name = pmid7831290>{{cite journal | vauthors = Sidorenko SP, Law CL, Chandran KA, Clark EA | title = Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 2 | pages = 359–63 | date = Jan 1995 | pmid = 7831290 | pmc = 42739 | doi = 10.1073/pnas.92.2.359 }}</ref>
* [[Syk]],<ref name = pmid7831290>{{cite journal | vauthors = Sidorenko SP, Law CL, Chandran KA, Clark EA | title = Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 2 | pages = 359–63 | date = Jan 1995 | pmid = 7831290 | pmc = 42739 | doi = 10.1073/pnas.92.2.359 | bibcode = 1995PNAS...92..359S | doi-access = free }}</ref>
* [[TRPV4]],<ref name = pmid12538589>{{cite journal | vauthors = Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM | title = Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11520–7 | date = Mar 2003 | pmid = 12538589 | doi = 10.1074/jbc.M211061200 }}</ref> and
* [[TRPV4]],<ref name = pmid12538589>{{cite journal | vauthors = Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM | title = Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11520–7 | date = Mar 2003 | pmid = 12538589 | doi = 10.1074/jbc.M211061200 | doi-access = free }}</ref>
* [[Protein unc-119 homolog|UNC119]].<ref name = pmid12496276>{{cite journal | vauthors = Cen O, Gorska MM, Stafford SJ, Sur S, Alam R | title = Identification of UNC119 as a novel activator of SRC-type tyrosine kinases | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8837–45 | date = Mar 2003 | pmid = 12496276 | doi = 10.1074/jbc.M208261200 }}</ref>
* [[Protein unc-119 homolog|UNC119]],<ref name = pmid12496276>{{cite journal | vauthors = Cen O, Gorska MM, Stafford SJ, Sur S, Alam R | title = Identification of UNC119 as a novel activator of SRC-type tyrosine kinases | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8837–45 | date = Mar 2003 | pmid = 12496276 | doi = 10.1074/jbc.M208261200 | doi-access = free }}</ref>

{{Div col end}}
{{Div col end}}


Line 53: Line 59:
* {{cite journal | vauthors = Jouvin MH, Numerof RP, Kinet JP | title = Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI | journal = Seminars in Immunology | volume = 7 | issue = 1 | pages = 29–35 | date = Feb 1995 | pmid = 7612892 | doi = 10.1016/1044-5323(95)90005-5 }}
* {{cite journal | vauthors = Jouvin MH, Numerof RP, Kinet JP | title = Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI | journal = Seminars in Immunology | volume = 7 | issue = 1 | pages = 29–35 | date = Feb 1995 | pmid = 7612892 | doi = 10.1016/1044-5323(95)90005-5 }}
* {{cite journal | vauthors = Hibbs ML, Dunn AR | title = Lyn, a src-like tyrosine kinase | journal = The International Journal of Biochemistry & Cell Biology | volume = 29 | issue = 3 | pages = 397–400 | date = Mar 1997 | pmid = 9202419 | doi = 10.1016/S1357-2725(96)00104-5 }}
* {{cite journal | vauthors = Hibbs ML, Dunn AR | title = Lyn, a src-like tyrosine kinase | journal = The International Journal of Biochemistry & Cell Biology | volume = 29 | issue = 3 | pages = 397–400 | date = Mar 1997 | pmid = 9202419 | doi = 10.1016/S1357-2725(96)00104-5 }}
* {{cite journal | last1= Blasioli |first1=J.|last2= Goodnow |first2=C. C. | title = Lyn/CD22/SHP-1 and Their Importance in Autoimmunity | journal = Current Directions in Autoimmunity | volume = 5 | issue = | pages = 151–60 | year = 2002 | pmid = 11826756 | doi = 10.1159/000060551 | isbn = 3-8055-7308-1 }}
* {{cite book | last1= Blasioli |first1=J.|last2= Goodnow |first2=C. C. | title = Lyn/CD22/SHP-1 and Their Importance in Autoimmunity | journal = Current Directions in Autoimmunity | volume = 5 | pages = 151–60 | year = 2002 | pmid = 11826756 | doi = 10.1159/000060551 | isbn = 978-3-8055-7308-5 }}
* {{cite journal | vauthors = Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M | title = HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication | journal = Journal of Biosciences | volume = 28 | issue = 3 | pages = 323–35 | date = Apr 2003 | pmid = 12734410 | doi = 10.1007/BF02970151 }}
* {{cite journal | vauthors = Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M | title = HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication | journal = Journal of Biosciences | volume = 28 | issue = 3 | pages = 323–35 | date = Apr 2003 | pmid = 12734410 | doi = 10.1007/BF02970151 | s2cid = 33749514 }}
* {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef | journal = Current HIV Research | volume = 2 | issue = 2 | pages = 141–51 | date = Apr 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}
* {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef | journal = Current HIV Research | volume = 2 | issue = 2 | pages = 141–51 | date = Apr 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}
* {{cite journal | vauthors = Joseph AM, Kumar M, Mitra D | title = Nef: "necessary and enforcing factor" in HIV infection | journal = Current HIV Research | volume = 3 | issue = 1 | pages = 87–94 | date = Jan 2005 | pmid = 15638726 | doi = 10.2174/1570162052773013 }}
* {{cite journal | vauthors = Joseph AM, Kumar M, Mitra D | title = Nef: "necessary and enforcing factor" in HIV infection | journal = Current HIV Research | volume = 3 | issue = 1 | pages = 87–94 | date = Jan 2005 | pmid = 15638726 | doi = 10.2174/1570162052773013 }}
* {{cite journal | vauthors = Stove V, Verhasselt B | title = Modelling thymic HIV-1 Nef effects | journal = Current HIV Research | volume = 4 | issue = 1 | pages = 57–64 | date = Jan 2006 | pmid = 16454711 | doi = 10.2174/157016206775197583 }}
* {{cite journal | vauthors = Stove V, Verhasselt B | title = Modelling thymic HIV-1 Nef effects | journal = Current HIV Research | volume = 4 | issue = 1 | pages = 57–64 | date = Jan 2006 | pmid = 16454711 | doi = 10.2174/157016206775197583 }}
{{refend}}
{{refend}}

== External links ==
* {{PDBe-KB2|P07948|Tyrosine-protein kinase Lyn}}


{{PDB Gallery|geneid=4067}}
{{PDB Gallery|geneid=4067}}
{{Tyrosine kinases}}
{{Tyrosine kinases}}
{{Enzymes}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
{{Portal bar|Biology|border=no}}


[[Category:EC 2.7.10]]
[[Category:EC 2.7.10]]

Revision as of 13:31, 4 April 2024

For other uses, see Lyn (disambiguation).
LYN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLYN, LYN proto-oncogene, Src family tyrosine kinase, JTK8, p53Lyn, p56Lyn
External IDsOMIM: 165120; MGI: 96892; HomoloGene: 55649; GeneCards: LYN; OMA:LYN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4067

17096

Ensembl

ENSG00000254087

ENSMUSG00000042228

UniProt

P07948

P25911

RefSeq (mRNA)

NM_001111097
NM_002350

NM_001111096
NM_010747

RefSeq (protein)

NP_001104567
NP_002341

NP_001104566
NP_034877

Location (UCSC)Chr 8: 55.88 – 56.01 MbChr 4: 3.68 – 3.81 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.[5]

Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells,[6] in neural tissues[7] liver, and adipose tissue.[8] In various hematopoietic cells, Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR),[9][10] CD40,[11] or CD19.[12] The abbreviation Lyn is derived from Lck/Yes novel tyrosine kinase, Lck and Yes also being members of the Src kinase family.

Function

Lyn has been described to have an inhibitory role in myeloid lineage proliferation.[13] Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation. LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase.[12][14] These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1,[15][16][17][18][19] which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.[20][21][22] HSP90 inhibitor NVP-BEP800 has been described to affect stability of LYN kinase and growth of B-cell acute lymphoblastic leukemias through inhibition of the NF-kappaB signaling. [23]

LYN is reported to be a key signal mediator for estrogen-dependent suppression of human osteoclast differentiation, survival, and function.[24] Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.[25] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.[26] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts.[27] This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.[27][28] Tolimidone (MLR-1023) is a small molecule allosteric activator of lyn kinase with an EC50 of 63 nM[29][30] that is currently under Phase 2a investigation for Type II diabetes.[31] In June, 2016, the sponsor of these studies, Melior Discovery, announced positive results from their Phase 2a study with tolimidone in diabetic patients,[32][33] and the continuation of additional clinical studies.[34]

Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration through the preservation of hepatocellular mitochondrial integrity.[35]

Several investigators have shown the role of lyn kinase in different aspects of pulmonary function. Lyn activation in pulmonary epithelium has been shown to be important in improving pulmonary barrier integrity and to reduce edema.[36][37] Additional evidence suggest that lyn activation in alveolar phagocytes improves phagocytosis of bacteria and reduces pulmonary infection. [38][39] Finally, other research has found that lyn activation reduces pulmonary hypersecretion of mucus. [40]


Pathology

Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and monocyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells.[13]

Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.[41]

Interactions

LYN has been shown to interact with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000254087 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042228 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K (Jan 1987). "The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck". Molecular and Cellular Biology. 7 (1): 237–43. doi:10.1128/MCB.7.1.237. PMC 365062. PMID 3561390.
  6. ^ Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K (Sep 1989). "Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I". Proceedings of the National Academy of Sciences of the United States of America. 86 (17): 6538–42. Bibcode:1989PNAS...86.6538Y. doi:10.1073/pnas.86.17.6538. PMC 297879. PMID 2505253.
  7. ^ Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T (Dec 1992). "Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system". Brain Research. Molecular Brain Research. 16 (3–4): 303–10. doi:10.1016/0169-328X(92)90239-8. PMID 1337939.
  8. ^ Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC (Feb 2010). "Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1". Cell Metabolism. 11 (2): 113–124. doi:10.1016/j.cmet.2009.12.010. PMC 2830006. PMID 20142099.
  9. ^ Yamamoto T, Yamanashi Y, Toyoshima K (Apr 1993). "Association of Src-family kinase Lyn with B-cell antigen receptor". Immunological Reviews. 132: 187–206. doi:10.1111/j.1600-065X.1993.tb00843.x. PMID 8349296. S2CID 10782326.
  10. ^ Campbell MA, Sefton BM (May 1992). "Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases". Molecular and Cellular Biology. 12 (5): 2315–21. doi:10.1128/MCB.12.5.2315. PMC 364403. PMID 1569953.
  11. ^ Ren CL, Morio T, Fu SM, Geha RS (Feb 1994). "Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2". The Journal of Experimental Medicine. 179 (2): 673–80. doi:10.1084/jem.179.2.673. PMC 2191357. PMID 7507510.
  12. ^ a b Campbell 1999
  13. ^ a b Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML (Oct 2001). "Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage". Immunity. 15 (4): 603–615. doi:10.1016/S1074-7613(01)00208-4. PMID 11672542.
  14. ^ Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, Yamamoto T (Feb 1992). "Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling". Proceedings of the National Academy of Sciences of the United States of America. 89 (3): 1118–22. Bibcode:1992PNAS...89.1118Y. doi:10.1073/pnas.89.3.1118. PMC 48397. PMID 1371009.
  15. ^ Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC (Apr 1998). "Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection". Immunity. 8 (4): 497–508. doi:10.1016/S1074-7613(00)80554-3. PMID 9586639.
  16. ^ Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT (Mar 1998). "Inhibition of the B cell by CD22: a requirement for Lyn". The Journal of Experimental Medicine. 187 (5): 807–11. doi:10.1084/jem.187.5.807. PMC 2212179. PMID 9480991.
  17. ^ Chan VW, Lowell CA, DeFranco AL (May 1998). "Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes". Current Biology. 8 (10): 545–53. Bibcode:1998CBio....8..545C. doi:10.1016/S0960-9822(98)70223-4. PMID 9601638. S2CID 12195731.
  18. ^ Nishizumi H, Horikawa K, Mlinaric-Rascan I, Yamamoto T (Apr 1998). "A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals". The Journal of Experimental Medicine. 187 (8): 1343–8. doi:10.1084/jem.187.8.1343. PMC 2212230. PMID 9547345.
  19. ^ Maeda A, Scharenberg AM, Tsukada S, Bolen JB, Kinet JP, Kurosaki T (Apr 1999). "Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1". Oncogene. 18 (14): 2291–7. doi:10.1038/sj.onc.1202552. PMID 10327049.
  20. ^ Lowell CA (Jul 2004). "Src-family kinases: rheostats of immune cell signaling". Molecular Immunology. 41 (6–7): 631–43. doi:10.1016/j.molimm.2004.04.010. PMID 15220000.
  21. ^ Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A (Mar 2003). "Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development". Nature Immunology. 4 (3): 274–9. doi:10.1038/ni893. PMID 12563261. S2CID 32559368.
  22. ^ Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM (Jan 2005). "Lyn tyrosine kinase: accentuating the positive and the negative". Immunity. 22 (1): 9–18. doi:10.1016/j.immuni.2004.12.004. PMID 15664155.
  23. ^ Mshaik R, Simonet J, Georgievski A, Jamal L, Bechoua S, Ballerini P, Bellaye PS, Mlamla Z, Pais de Barros JP, Geissler A, Francin PJ, Girodon F, Garrido C, Quéré R (March 2021). "HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemia". Blood Cancer J. 3 (11): 61. doi:10.1038/s41408-021-00450-2. PMC 7973815. PMID 33737511.
  24. ^ Gavali S, Gupta MK, Daswani B, Wani MR, Sirdeshmukh R, Khatkhatay MI (March 2019). "LYN, a key mediator in estrogen-dependent suppression of osteoclast differentiation, survival, and function". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865 (3): 547–557. doi:10.1016/j.bbadis.2018.12.016. PMID 30579930.
  25. ^ Müller G, Wied S, Frick W (Jul 2000). "Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes". Molecular and Cellular Biology. 20 (13): 4708–4723. doi:10.1128/mcb.20.13.4708-4723.2000. PMC 85892. PMID 10848597.
  26. ^ Anderwald C, Müller G, Koca G, Fürnsinn C, Waldhäusl W, Roden M (Jul 2002). "Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2". Molecular Endocrinology. 16 (7): 1612–1628. doi:10.1210/mend.16.7.0867. PMID 12089355.
  27. ^ a b Müller G (Nov 2000). "The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl". Molecular Medicine. 6 (11): 907–933. doi:10.1007/BF03401827. PMC 1949923. PMID 11147570.
  28. ^ Müller G, Schulz A, Wied S, Frick W (Mar 2005). "Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes". Biochemical Pharmacology. 69 (5): 761–780. doi:10.1016/j.bcp.2004.11.014. PMID 15710354.
  29. ^ Ochman AR, Lipinski CA, Handler JA, Reaume AG, Saporito MS (2012). "The Lyn kinase activator MLR-123 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes". J Pharmacol Exp Ther. 342 (1): 23–32. doi:10.1124/jpet.112.192187. PMID 22431203. S2CID 7288053.[permanent dead link]
  30. ^ Saporito MS, Ochman AR, Lipinski CA, Handler JA, Reaume AG (2011). "MLR-1023 is potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo". Journal of Pharmacology and Experimental Therapeutics. 342 (1): 15–22. doi:10.1124/jpet.112.192096. PMID 22473614. S2CID 26419896.
  31. ^ "Melior Pharmaceuticals Initiates Phase 2 Study with MLR-1023 for Type 2 Diabetes". Business Wire. 3 March 2015. Retrieved March 3, 2015.
  32. ^ "Melior Pharmaceuticals Announces Positive Phase 2A Results in Type 2 Diabetes Study". www.businesswire.com. 13 June 2016. Retrieved 2017-08-04.
  33. ^ Lee MK, Kim SG, Watkins E, Moon MK, Rhee SY, Frias JP, Chung CH, Lee SH, Block B, Cha BS, Park HK, Kim BJ, Greenway F (May 2020). "A Novel Non-PPARgamma Insulin Sensitizer: MLR-1023 Clinical Proof-of-concept in Type 2 Diabetes Mellitus". J. Diabetes Complications. 34 (5): 107555. doi:10.1016/j.jdiacomp.2020.107555. PMID 32019723. S2CID 211036334.
  34. ^ "Melior Discovery website press releases". Archived from the original on 2018-05-17. Retrieved 2018-06-11.
  35. ^ Gringeri E, Carraro A, Tibaldi E, D'Amico FE, Mancon M, Toninello A, Pagano MA, Vio C, Cillo U, Brunati AM (December 2009). "Lyn-mediated mitochondrial tyrosine phosphorylation is required to preserve mitochondrial integrity in early liver regeneration" (PDF). The Biochemical Journal. 425 (2): 401–12. doi:10.1042/BJ20090902. PMID 19832701.
  36. ^ Jan J, Zhang G, Welch EJ, Liang Y, Fu J, Vogel SM, Lowell CA, Du X, Cheresh DA, Malik AB, Li Z (Dec 2013). "A critical role for Lyn kinase in strengthening endothelial integrity and barrier function". Blood. 122 (25): 4140–4149. doi:10.1182/blood-2013-03-491423. PMC 3862279. PMID 24108461.
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  38. ^ Li X, He S, Zhou X, Ye Y, Tan S, Zhang S, Li R, Yu M, Jundt MC, Hidebrand A, Wang Y, Li G, Huang C, Wu M (Jan 2016). "Lyn delivers bacteria to lysosomes for eradication through TLR2-initiated autophagy related phagocytosis". PLOS Pathogens. 12 (1): e1005363. doi:10.1371/journal.ppat.1005363. PMC 4703367. PMID 26735693.
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Further reading

  • Overview of all the structural information available in the PDB for UniProt: P07948 (Tyrosine-protein kinase Lyn) at the PDBe-KB.
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