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{{Short description|Class of enzymes}}
{{Infobox enzyme
{{Infobox enzyme
| Name = Protein-tyrosine-phosphatase
| Name = Protein-tyrosine-phosphatase
| EC_number = 3.1.3.48
| EC_number = 3.1.3.48
| CAS_number = 79747-53-8
| CAS_number = 79747-53-8
| GO_code =
| IUBMB_EC_number = 3/1/3/48
| GO_code =
| image = 1xm2.jpg
| image = 1xm2.jpg
| width = 270
⚫
| caption = Protein tyrosine phosphatase 1, trimer, Human
| width = 270
⚫
| caption = Protein tyrosine phosphatase 1, trimer, Human
}}
}}
'''Protein tyrosine phosphatases''' (EC 3.1.3.48, systematic name '''protein-tyrosine-phosphate phosphohydrolase''') are a group of [[enzymes]] that remove [[phosphate]] groups from [[phosphorylated]] [[tyrosine]] residues on proteins:
⚫
'''Protein tyrosine phosphatases''' are a group of [[enzymes]] that remove [[phosphate]] groups from [[phosphorylated]] [[tyrosine]] residues on proteins. Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an [[Regulation of gene expression|appropriate level]] of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; {{EC number|3.1.3.48}}) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in [[signal transduction]] pathways (such as the [[MAPK/ERK pathway|MAP kinase pathway]]) and [[cell cycle]] control, and are important in the control of [[cell growth]], [[Cell proliferation|proliferation]], [[Cell differentiation|differentiation]], [[Cell transformation|transformation]], and [[synaptic plasticity]].<ref name="PUB00035793">{{cite journal |vauthors=Dixon JE, Denu JM |title=Protein tyrosine phosphatases: mechanisms of catalysis and regulation |journal=Curr Opin Chem Biol |volume=2 |issue=5 |pages=- |year=1998 |pmid=9818190}}</ref><ref name="PUB00035794">{{cite journal|vauthors=Paul S, Lombroso PJ |title=Receptor and nonreceptor protein tyrosine phosphatases in the nervous system |journal=Cell. Mol. Life Sci. |volume=60 |issue=11 |pages=- |year=2003 |pmid=14625689|doi=10.1007/s00018-003-3123-7}}</ref><ref name="ReferenceA">{{cite journal | vauthors = Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ | title = Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 44 | pages = 19014–9 | date = Nov 2010 | pmid = 20956308 | pmc = 2973892 | doi = 10.1073/pnas.1013543107 }}</ref><ref name="Goebel-Goody SM 2012">{{cite journal | vauthors = Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ | title = Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model | journal = Genes, Brain, and Behavior | volume = 11 | issue = 5 | pages = 586–600 | date = Jul 2012 | pmid = 22405502 | pmc = 3922131 | doi = 10.1111/j.1601-183X.2012.00781.x }}</ref>

:[a protein]-tyrosine phosphate + H<sub>2</sub>O = [a protein]-tyrosine + phosphate

⚫
Protein tyrosine (pTyr) phosphorylation is a common [[post-translational modification]] that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an [[Regulation of gene expression|appropriate level]] of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; {{EC number|3.1.3.48}}) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in [[signal transduction]] pathways (such as the [[MAPK/ERK pathway|MAP kinase pathway]]) and [[cell cycle]] control, and are important in the control of [[cell growth]], [[Cell proliferation|proliferation]], [[Cell differentiation|differentiation]], [[Cell transformation|transformation]], and [[synaptic plasticity]].<ref name="PUB00035793">{{cite journal |vauthors=Dixon JE, Denu JM |year=2018 |title=Protein tyrosine phosphatases: mechanisms of catalysis and regulation |journal=Curr Opin Chem Biol |volume=2 |issue=5 |pages=633–41 |doi=10.1016/S1367-5931(98)80095-1 |pmid=9818190}}</ref><ref name="PUB00035794">{{cite journal |vauthors=Paul S, Lombroso PJ |year=2020 |title=Receptor and nonreceptor protein tyrosine phosphatases in the nervous system |journal=Cell. Mol. Life Sci. |volume=60 |issue=11 |pages=2465–82 |doi=10.1007/s00018-003-3123-7 |pmid=14625689 |s2cid=10827975|pmc=11138652 }}</ref><ref name="ReferenceA">{{cite journal |vauthors=Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ |date=Nov 2018 |title=Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=107 |issue=44 |pages=19014–9 |bibcode=2010PNAS..10719014Z |doi=10.1073/pnas.1013543107 |pmc=2973892 |pmid=20956308 |doi-access=free}}</ref><ref name="Goebel-Goody SM 2012">{{cite journal |vauthors=Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ |date=Jul 2019 |title=Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model |journal=Genes, Brain and Behavior |volume=11 |issue=5 |pages=586–600 |doi=10.1111/j.1601-183X.2012.00781.x |pmc=3922131 |pmid=22405502}}</ref>


==Functions==
==Functions==
Together with [[tyrosine kinase]]s, PTPs regulate the [[phosphorylation]] state of many important [[Signalling (biology)|signalling]] molecules, such as the [[MAP kinase]] family.
Together with [[tyrosine kinase]]s, PTPs regulate the [[phosphorylation]] state of many important [[Cell signaling|signalling]] molecules, such as the [[MAP kinase]] family.
PTPs are increasingly viewed as integral components of [[signal transduction]] cascades, despite less study and understanding compared to [[tyrosine kinase]]s.
PTPs are increasingly viewed as integral components of [[signal transduction]] cascades, despite less study and understanding compared to [[tyrosine kinase]]s.


PTPs have been implicated in regulation of many cellular processes, including, but not limited to:
PTPs have been implicated in regulation of many cellular processes, including, but not limited to:
*[[Cell growth]]
* [[Cell growth]]
*[[Cellular differentiation]]
* [[Cellular differentiation]]
*[[Mitosis|Mitotic]] cycles
* [[Mitosis|Mitotic]] cycles
*[[Oncogenic]] [[Transformation (genetics)|transformation]]
* [[Oncogenic]] [[Transformation (genetics)|transformation]]
*[[Receptor endocytosis]]<ref>{{cite journal | vauthors = Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ | title = Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61 | journal = The Journal of Neuroscience | volume = 30 | issue = 17 | pages = 5948–57 | date = Apr 2010 | pmid = 20427654 | pmc = 2868326 | doi = 10.1523/JNEUROSCI.0157-10.2010 }}</ref>
* [[Receptor endocytosis]]<ref>{{cite journal |vauthors=Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ |date=Apr 2022 |title=Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61 |journal=The Journal of Neuroscience |volume=30 |issue=17 |pages=5948–57 |doi=10.1523/JNEUROSCI.0157-10.2010 |pmc=2868326 |pmid=20427654}}</ref>


==Classification==
==Classification==


===By mechanism===
===By mechanism===
PTP activity can be found in four protein families.<ref name="PUB00035795">{{cite journal |vauthors=Sun JP, Zhang ZY, Wang WQ |title=An overview of the protein tyrosine phosphatase superfamily |journal=Curr Top Med Chem |volume=3 |issue=7 |pages=- |year=2003 |pmid=12678841}}</ref><ref>{{cite journal |vauthors=Alonso A, Sasin J, etal | title = Protein tyrosine phosphatases in the human genome | journal = Cell | year=2004 | volume=117 | issue=6 | pages=699–711 | pmid = 15186772 | doi = 10.1016/j.cell.2004.05.018}}</ref>
PTP activity can be found in four protein families.<ref name="PUB00035795">{{cite journal |vauthors=Sun JP, Zhang ZY, Wang WQ |year=2017 |title=An overview of the protein tyrosine phosphatase superfamily |journal=Curr Top Med Chem |volume=3 |issue=7 |pages=739–48 |doi=10.2174/1568026033452302 |pmid=12678841}}</ref><ref>{{cite journal |vauthors=Alonso A, Sasin J, etal |year=2020 |title=Protein tyrosine phosphatases in the human genome |journal=Cell |volume=117 |issue=6 |pages=699–711 |doi=10.1016/j.cell.2004.05.018 |pmid=15186772 |doi-access=free}}</ref>


Links to all 107 members of the protein tyrosine phosphatase family can be found in the [[template:Protein tyrosine phosphatases|template]] at the bottom of this article.
Links to all 107 members of the protein tyrosine phosphatase family can be found in the [[template:Protein tyrosine phosphatases|template]] at the bottom of this article.


====Class I====
====Class I====
The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into
The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into
* 38 classical PTPs
* 38 classical PTPs
** 21 [[receptor tyrosine phosphatase]]
** 21 [[receptor tyrosine phosphatase]]s
** 17 nonreceptor-type PTPs
** 17 nonreceptor-type PTPs
* 61 VH-1-like or dual-specific phosphatases (DSPs)
* 61 VH-1-like or dual-specific phosphatases (DSPs)
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** 4 CDC14s
** 4 CDC14s
** 19 atypical DSPs
** 19 atypical DSPs
** 5 [[PTEN (gene)|Phosphatase and tensin homolog]]s (PTENs)
** 5 [[PTEN (gene)|phosphatase and tensin homolog]]s (PTENs)
** 16 [[Myotubularin]]s
** 16 [[myotubularin]]s


Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine [[phosphatases]]. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr ({{EC number|3.1.3.16}}) and tyrosine-specific protein phosphatase ({{EC number|3.1.3.48}}) activity able to remove the [[serine]]/[[threonine]] or the tyrosine-bound phosphate group from a wide range of [[phosphoproteins]], including a number of enzymes that have been phosphorylated under the action of a [[kinase]]. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.
Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine [[phosphatase]]s. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr ({{EC number|3.1.3.16}}) and tyrosine-specific protein phosphatase ({{EC number|3.1.3.48}}) activity able to remove the [[serine]]/[[threonine]] or the tyrosine-bound phosphate group from a wide range of [[phosphoprotein]]s, including a number of enzymes that have been phosphorylated under the action of a [[kinase]]. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.


[[LEOPARD syndrome]], [[Noonan syndrome]], and [[Metachondromatosis]] are associated with ''[[PTPN11]]''.
[[LEOPARD syndrome]], [[Noonan syndrome]], and [[metachondromatosis]] are associated with ''[[PTPN11]]''.


Elevated levels of activated [[PTPN5]] negatively affects [[synaptic stability]] and plays a role in [[Alzheimer’s disease]],<ref name="ReferenceA"/> [[Fragile X Syndrome]]<ref name="Goebel-Goody SM 2012"/> [[schizophrenia]],<ref>{{cite journal | vauthors = Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ | title = The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications | journal = Translational Psychiatry | volume = 2 | issue = 7 | pages = e137 | year = 2012 | pmid = 22781170 | pmc = 3410627 | doi = 10.1038/tp.2012.63 }}</ref> and [[Parkinson’s disease]].<ref>{{cite journal | vauthors = Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC | title = STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 4 | pages = 1202–7 | date = Jan 2015 | pmid = 25583483 | pmc = 4313846 | doi = 10.1073/pnas.1417423112 }}</ref> Decreased levels of [[PTPN5]] has been implicated in [[Huntington's disease]],<ref>{{cite journal | vauthors = Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J, Pérez-Navarro E | title = Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity | journal = The Journal of Neuroscience | volume = 31 | issue = 22 | pages = 8150–62 | date = Jun 2011 | pmid = 21632937 | pmc = 3472648 | doi = 10.1523/JNEUROSCI.3446-10.2011 }}</ref><ref>{{cite journal | vauthors = Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA | title = Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model | journal = Human Molecular Genetics | volume = 21 | issue = 17 | pages = 3739–52 | date = Sep 2012 | pmid = 22523092 | pmc = 3412376 | doi = 10.1093/hmg/dds154 }}</ref> [[cerebral ischemia]]<ref>{{cite journal | vauthors = Deb I, Manhas N, Poddar R, Rajagopal S, Allan AM, Lombroso PJ, Rosenberg GA, Candelario-Jalil E, Paul S | title = Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia | journal = The Journal of Neuroscience | volume = 33 | issue = 45 | pages = 17814–26 | date = Nov 2013 | pmid = 24198371 | pmc = 3818554 | doi = 10.1523/JNEUROSCI.2346-12.2013 }}</ref> [[alcohol abuse]],<ref>{{cite journal | vauthors = Hicklin TR, Wu PH, Radcliffe RA, Freund RK, Goebel-Goody SM, Correa PR, Proctor WR, Lombroso PJ, Browning MD | title = Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 16 | pages = 6650–5 | date = Apr 2011 | pmid = 21464302 | pmc = 3081035 | doi = 10.1073/pnas.1017856108 }}</ref><ref>{{cite journal | vauthors = Darcq E, Hamida SB, Wu S, Phamluong K, Kharazia V, Xu J, Lombroso P, Ron D | title = Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption | journal = Journal of Neurochemistry | volume = 129 | issue = 6 | pages = 1024–34 | date = Jun 2014 | pmid = 24588427 | pmc = 4055745 | doi = 10.1111/jnc.12701 }}</ref> and [[stress (psychological)|stress]] disorders.<ref>{{cite journal | vauthors = Yang CH, Huang CC, Hsu KS | title = A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes | journal = The Journal of Neuroscience | volume = 32 | issue = 22 | pages = 7550–62 | date = May 2012 | pmid = 22649233 | doi = 10.1523/JNEUROSCI.5902-11.2012 }}</ref><ref>{{cite journal | vauthors = Dabrowska J, Hazra R, Guo JD, Li C, Dewitt S, Xu J, Lombroso PJ, Rainnie DG | title = Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis | journal = Biological Psychiatry | volume = 74 | issue = 11 | pages = 817–26 | date = Dec 2013 | pmid = 24012328 | pmc = 3818357 | doi = 10.1016/j.biopsych.2013.07.032 }}</ref> Together these findings indicate that only at optimal levels of [[PTPN5]] is synaptic function unimpaired.
Elevated levels of activated [[PTPN5]] negatively affects [[synaptic stability]] and plays a role in [[Alzheimer's disease]],<ref name="ReferenceA"/> [[Fragile X syndrome]],<ref name="Goebel-Goody SM 2012"/> [[schizophrenia]],<ref>{{cite journal |vauthors=Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ |year=2021 |title=The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications |journal=Translational Psychiatry |volume=2 |issue=7 |pages=e137 |doi=10.1038/tp.2012.63 |pmc=3410627 |pmid=22781170}}</ref> and [[Parkinson's disease]].<ref>{{cite journal |vauthors=Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC |date=Jan 2018 |title=STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=112 |issue=4 |pages=1202–7 |bibcode=2015PNAS..112.1202K |doi=10.1073/pnas.1417423112 |pmc=4313846 |pmid=25583483 |doi-access=free}}</ref> Decreased levels of [[PTPN5]] has been implicated in [[Huntington's disease]],<ref>{{cite journal |vauthors=Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas JJ, Lombroso PJ, Alberch J, Pérez-Navarro E |date=Jun 2021 |title=Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity |journal=The Journal of Neuroscience |volume=31 |issue=22 |pages=8150–62 |doi=10.1523/JNEUROSCI.3446-10.2011 |pmc=3472648 |pmid=21632937}}</ref><ref>{{cite journal |vauthors=Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA |date=Sep 2020 |title=Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model |journal=Human Molecular Genetics |volume=21 |issue=17 |pages=3739–52 |doi=10.1093/hmg/dds154 |pmc=3412376 |pmid=22523092}}</ref> [[brain ischemia]],<ref>{{cite journal |vauthors=Deb I, Manhas N, Poddar R, Rajagopal S, Allan AM, Lombroso PJ, Rosenberg GA, Candelario-Jalil E, Paul S |date=Nov 2020 |title=Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia |journal=The Journal of Neuroscience |volume=33 |issue=45 |pages=17814–26 |doi=10.1523/JNEUROSCI.2346-12.2013 |pmc=3818554 |pmid=24198371}}</ref> [[alcohol use disorder]],<ref>{{cite journal |vauthors=Hicklin TR, Wu PH, Radcliffe RA, Freund RK, Goebel-Goody SM, Correa PR, Proctor WR, Lombroso PJ, Browning MD |date=Apr 2020 |title=Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=108 |issue=16 |pages=6650–5 |bibcode=2011PNAS..108.6650H |doi=10.1073/pnas.1017856108 |pmc=3081035 |pmid=21464302 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Darcq E, Hamida SB, Wu S, Phamluong K, Kharazia V, Xu J, Lombroso P, Ron D |date=Jun 2019 |title=Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption |journal=Journal of Neurochemistry |volume=129 |issue=6 |pages=1024–34 |doi=10.1111/jnc.12701 |pmc=4055745 |pmid=24588427}}</ref> and [[stress (psychological)|stress]] disorders.<ref>{{cite journal |vauthors=Yang CH, Huang CC, Hsu KS |date=May 2022 |title=A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes |journal=The Journal of Neuroscience |volume=32 |issue=22 |pages=7550–62 |doi=10.1523/JNEUROSCI.5902-11.2012 |pmc=6703597 |pmid=22649233 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Dabrowska J, Hazra R, Guo JD, Li C, Dewitt S, Xu J, Lombroso PJ, Rainnie DG |date=Dec 2020 |title=Striatal-enriched protein tyrosine phosphatase-STEPs toward understanding chronic stress-induced activation of corticotrophin releasing factor neurons in the rat bed nucleus of the stria terminalis |journal=Biological Psychiatry |volume=74 |issue=11 |pages=817–26 |doi=10.1016/j.biopsych.2013.07.032 |pmc=3818357 |pmid=24012328}}</ref> Together these findings indicate that only at optimal levels of [[PTPN5]] is synaptic function unimpaired.


====Class II====
====Class II====
LMW (low-molecular-weight) phosphatases, or [[acid phosphatases]], act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic [[acyl]] phosphates.<ref name="PUB00002706">{{cite journal |vauthors=Wo YY, Shabanowitz J, Hunt DF, Davis JP, Mitchell GL, Van Etten RL, McCormack AL |title=Sequencing, cloning, and expression of human red cell-type acid phosphatase, a cytoplasmic phosphotyrosyl protein phosphatase |journal=J. Biol. Chem. |volume=267 |issue=15 |pages=10856–10865 |year=1992 |pmid=1587862}}</ref><ref name="PUB00005003">{{cite journal |vauthors=Shekels LL, Smith AJ, Bernlohr DA, Van Etten RL |title=Identification of the adipocyte acid phosphatase as a PAO-sensitive tyrosyl phosphatase |journal=Protein Sci. |volume=1 |issue=6 |pages=710–721 |year=1992 |pmid=1304913 |pmc=2142247 |doi=10.1002/pro.5560010603}}</ref>
LMW (low-molecular-weight) phosphatases, or [[acid phosphatases]], act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic [[acyl]] phosphates.<ref name="PUB00002706">{{cite journal |vauthors=Wo YY, Shabanowitz J, Hunt DF, Davis JP, Mitchell GL, Van Etten RL, McCormack AL |year=2023 |title=Sequencing, cloning, and expression of human red cell-type acid phosphatase, a cytoplasmic phosphotyrosyl protein phosphatase |journal=J. Biol. Chem. |volume=267 |issue=15 |pages=10856–10865 |doi=10.1016/S0021-9258(19)50097-7 |pmid=1587862 |doi-access=free}}</ref><ref name="PUB00005003">{{cite journal |vauthors=Shekels LL, Smith AJ, Bernlohr DA, Van Etten RL |title=Identification of the adipocyte acid phosphatase as a PAO-sensitive tyrosyl phosphatase |journal=Protein Sci. |volume=1 |issue=6 |pages=710–721 |year=1992 |pmid=1304913 |pmc=2142247 |doi=10.1002/pro.5560010603}}</ref>


The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase ([[LMPTP]]).
The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase ([[LMPTP]]).
Line 60: Line 64:


====Class IV====
====Class IV====
These are members of the [[Haloacid dehydrogenase superfamily|HAD]] fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes.<ref name="ChenManning">{{cite journal |vauthors=Chen MJ, Dixon JE, Manning G |date=April 2023 |title=Genomics and evolution of protein phosphatases |journal=Science Signaling |volume=10 |issue=474 |pages=eaag1796 |doi=10.1126/scisignal.aag1796 |pmid=28400531 |s2cid=41041971}}</ref> The subfamily EYA (eyes absent) is believed to be pTyr-specific, and has four members in human, [[EYA1]], [[EYA2]], EYA3, and [[EYA4]]. This class has a distinct catalytic mechanism from the other three classes.<ref name="PlaxtonMcManus2006">{{cite book |last1=Plaxton |first1=William C. |url=https://books.google.com/books?id=U-8GgunwoRYC&pg=PA130 |title=Control of primary metabolism in plants |last2=McManus |first2=Michael T. |publisher=Wiley-Blackwell |year=2020 |isbn=978-1-4051-3096-7 |pages=130– |access-date=12 December 2020 |name-list-style=vanc}}</ref>
pTyr-specific phosphatases

The class IV PTPs contains four members, [[EYA1|Eya1-4]].

This class is believed to have evolved separately from the other three.<ref name="PlaxtonMcManus2006">{{cite book|author1=William C. Plaxton|author2=Michael T. McManus|title=Control of primary metabolism in plants|url=http://books.google.com/books?id=U-8GgunwoRYC&pg=PA130|accessdate=12 December 2010|year=2006|publisher=Wiley-Blackwell|isbn=978-1-4051-3096-7|pages=130–}}</ref>


===By location===
===By location===
Based on their cellular localization, PTPases are also classified as:
Based on their cellular localization, PTPases are also classified as:
⚫
* Receptor-like, which are [[transmembrane receptors]] that contain PTPase [[Protein domains|domains]].<ref name="PUB00035796">{{cite journal |vauthors=Knapp S, Longman E, Debreczeni JE, Eswaran J, Barr AJ |title=The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1 |journal=Protein Sci. |volume=15 |issue=6|pages= 1500–1505|year=2006 |pmid=16672235 |doi=10.1110/ps.062128706 |pmc=2242534}}</ref> In terms of structure, all known receptor PTPases are made up of a variable-length [[extracellular domain]], followed by a [[transmembrane]] region and a [[C-terminal]] [[catalytic]] [[cytoplasmic]] domain. Some of the receptor PTPases contain [[fibronectin]] type III (FN-III) repeats, [[immunoglobulin]]-like domains, MAM domains, or [[carbonic anhydrase]]-like domains in their extracellular region. In general, the cytoplasmic region contains two copies of the PTPase domain. The first seems to have enzymatic activity, whereas the second is inactive.

⚫
* Non-receptor (intracellular) PTPases<ref name="PUB00035797">{{cite journal |author=[[Perrimon N]], Johnson MR, Perkins LA, Melnick MB |year=2018 |title=The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila |journal=Dev. Biol. |volume=180 |issue=1 |pages=63–81 |doi=10.1006/dbio.1996.0285 |pmid=8948575 |doi-access=free}}</ref>
⚫
* Receptor-like, which are [[transmembrane receptors]] that contain PTPase [[Protein domains|domains]].<ref name="PUB00035796">{{cite journal |vauthors=Knapp S, Longman E, Debreczeni JE, Eswaran J, Barr AJ |title=The crystal structure of human receptor protein tyrosine phosphatase kappa phosphatase domain 1 |journal=Protein Sci. |volume=15 |issue=6|pages=- |year=2006 |pmid=16672235 |doi=10.1110/ps.062128706 |pmc=2242534}}</ref> In terms of structure, all known receptor PTPases are made up of a variable-length [[extracellular domain]], followed by a [[transmembrane]] region and a [[C-terminal]] [[catalytic]] [[cytoplasmic]] domain. Some of the receptor PTPases contain [[fibronectin]] type III (FN-III) repeats, [[immunoglobulin]]-like domains, MAM domains, or [[carbonic anhydrase]]-like domains in their extracellular region. In general, the cytoplasmic region contains two copies of the PTPase domain. The first seems to have enzymatic activity, whereas the second is inactive.
⚫
* Non-receptor (intracellular) PTPases<ref name="PUB00035797">{{cite journal |author=[[Perrimon N]], Johnson MR, Perkins LA, Melnick MB |title=The nonreceptor protein tyrosine phosphatase corkscrew functions in multiple receptor tyrosine kinase pathways in Drosophila |journal=Dev. Biol. |volume=180 |issue=1 |pages=- |year=1996 |pmid=8948575 |doi=10.1006/dbio.1996.0285}}</ref>


===Common elements===
===Common elements===
All PTPases, other than those of the eya family, carry the highly conserved active site [[Sequence motif|motif]] C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel [[beta-sheet]] with flanking [[alpha-helices]] containing a beta-loop-alpha-loop that encompasses the PTP signature motif.<ref name="PUB00035798">{{cite journal |vauthors=Barford D, Das AK, Egloff MP |title=The structure and mechanism of protein phosphatase s: insights into catalysis and regulation |journal=Annu. Rev. Biophys. Biomol. Struct. |volume=27 |issue= 1|pages=- |year=1998 |pmid=9646865 |doi=10.1146/annurev.biophys.27.1.133}}</ref> Functional diversity between PTPases is endowed by regulatory domains and subunits.
All PTPases, other than those of the EYA family, carry the highly conserved active site [[Sequence motif|motif]] C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel [[beta-sheet]] with flanking [[alpha-helices]] containing a beta-loop-alpha-loop that encompasses the PTP signature motif.<ref name="PUB00035798">{{cite journal |vauthors=Barford D, Das AK, Egloff MP |year=2021 |title=The structure and mechanism of protein phosphatase s: insights into catalysis and regulation |journal=Annu. Rev. Biophys. Biomol. Struct. |volume=27 |issue=1 |pages=133–64 |doi=10.1146/annurev.biophys.27.1.133 |pmid=9646865}}</ref> Functional diversity between PTPases is endowed by regulatory domains and subunits.


{|
{|
|- valign=top
|- valign=top
|{{Pfam box
|{{Pfam box
| Symbol = LMWPc
| Symbol = LMWPc
| Name = Low-molecular-weight phosphotyrosine protein phosphatase
| Name = Low-molecular-weight phosphotyrosine protein phosphatase
| image = PDB 1phr EBI.jpg
| image = PDB 1phr EBI.jpg
| width =
| width =
| caption = Structure of a low-molecular-weight phosphotyrosine protein phosphatase.<ref name="pmid8052313">{{cite journal |vauthors=Su XD, Taddei N, Stefani M, Ramponi G, Nordlund P |title=The crystal structure of a low-molecular-weight phosphotyrosine protein phosphatase |journal=Nature |volume=370 |issue=6490 |pages=575–8 |date=August 1994 |pmid=8052313 |doi=10.1038/370575a0 |url=}}</ref>
| caption = Structure of a low-molecular-weight phosphotyrosine protein phosphatase.<ref name="pmid8052313">{{cite journal |vauthors=Su XD, Taddei N, Stefani M, Ramponi G, Nordlund P |title=The crystal structure of a low-molecular-weight phosphotyrosine protein phosphatase |journal=Nature |volume=370 |issue=6490 |pages=575–8 |date=August 1994 |pmid=8052313 |doi=10.1038/370575a0 |bibcode=1994Natur.370..575S |s2cid=4310667 }}</ref>
| Pfam = PF01451
| Pfam = PF01451
| InterPro = IPR017867
| InterPro = IPR017867
| SMART = SM00226
| SMART = SM00226
| SCOP = 1phr
| SCOP = 1phr
| CDD = cd00115
| PDB = {{PDB2|1bvh}}, {{PDB2|1c0e}}, {{PDB2|1d1p}}, {{PDB2|1d1q}}, {{PDB2|1d2a}}, {{PDB2|1dg9}}, {{PDB2|1jf8}}, {{PDB2|1jfv}}, {{PDB2|1jl3}}, {{PDB2|1ljl}}
| PDB = {{PDB2|1bvh}}, {{PDB2|1c0e}}, {{PDB2|1d1p}}, {{PDB2|1d1q}}, {{PDB2|1d2a}}, {{PDB2|1dg9}}, {{PDB2|1jf8}}, {{PDB2|1jfv}}, {{PDB2|1jl3}}, {{PDB2|1ljl}}
}}
}}
|{{Pfam box
|{{Pfam box
| Symbol = Y_phosphatase
| Symbol = Y_phosphatase
| Name = Protein-tyrosine phosphatase
| Name = Protein-tyrosine phosphatase
| image = PDB 1ypt EBI.jpg
| image = PDB 1ypt EBI.jpg
| caption = Structure of Yersinia protein tyrosine phosphatase.<ref name="pmid8052312">{{cite journal |vauthors=Stuckey JA, Schubert HL, Fauman EB, Zhang ZY, Dixon JE, Saper MA |title=Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 A and the complex with tungstate |journal=Nature |volume=370 |issue=6490 |pages=571–5 |date=August 1994 |pmid=8052312 |doi=10.1038/370571a0 |url=}}</ref>
| caption = Structure of Yersinia protein tyrosine phosphatase.<ref name="pmid8052312">{{cite journal |vauthors=Stuckey JA, Schubert HL, Fauman EB, Zhang ZY, Dixon JE, Saper MA |title=Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 A and the complex with tungstate |journal=Nature |volume=370 |issue=6490 |pages=571–5 |date=August 1994 |pmid=8052312 |doi=10.1038/370571a0 |bibcode=1994Natur.370..571S |url=https://deepblue.lib.umich.edu/bitstream/2027.42/62819/1/370571a0.pdf|hdl=2027.42/62819 |s2cid=4332099 |hdl-access=free }}</ref>
| Pfam = PF00102
| Pfam = PF00102
| Pfam_clan = CL0031
| Pfam_clan = CL0031
| InterPro = IPR000242
| InterPro = IPR000242
| SMART = SM00194
| SMART = SM00194
| SCOP = 1ypt
| SCOP = 1ypt
| PROSITE = PS50055
| PROSITE = PS50055
| CDD = cd00047
| PDB = {{PDB2|1a5y}}, {{PDB2|1aax}}, {{PDB2|1bzc}}, {{PDB2|1bzh}}, {{PDB2|1bzj}}, {{PDB2|1c83}}, {{PDB2|1c84}}, {{PDB2|1c85}}, {{PDB2|1c86}}, {{PDB2|1c87}}
| PDB = {{PDB2|1a5y}}, {{PDB2|1aax}}, {{PDB2|1bzc}}, {{PDB2|1bzh}}, {{PDB2|1bzj}}, {{PDB2|1c83}}, {{PDB2|1c84}}, {{PDB2|1c85}}, {{PDB2|1c86}}, {{PDB2|1c87}}
}}
}}
|{{Pfam box
|{{Pfam box
| Symbol = DSPc
| Symbol = DSPc
| Name = Dual-specificity phosphatase, catalytic domain
| Name = Dual-specificity phosphatase, catalytic domain
| image = PDB 1vhr EBI.jpg
| image = PDB 1vhr EBI.jpg
| caption = Structure of the dual-specificity protein phosphatase VHR.<ref name="pmid8650541">{{cite journal |vauthors=Yuvaniyama J, Denu JM, Dixon JE, Saper MA |title=Crystal structure of the dual specificity protein phosphatase VHR |journal=Science |volume=272 |issue=5266 |pages=1328–31 |date=May 1996 |pmid=8650541 |doi= 10.1126/science.272.5266.1328|url=}}</ref>
| caption = Structure of the dual-specificity protein phosphatase VHR.<ref name="pmid8650541">{{cite journal |vauthors=Yuvaniyama J, Denu JM, Dixon JE, Saper MA |title=Crystal structure of the dual specificity protein phosphatase VHR |journal=Science |volume=272 |issue=5266 |pages=1328–31 |date=May 1996 |pmid=8650541 |doi= 10.1126/science.272.5266.1328|bibcode=1996Sci...272.1328Y |s2cid=33816598 }}</ref>
| Pfam = PF00782
| Pfam = PF00782
| Pfam_clan = CL0031
| Pfam_clan = CL0031
| InterPro = IPR000340
| InterPro = IPR000340
| SMART =
| SMART =
| SCOP = 1vhr
| SCOP = 1vhr
| PROSITE = PDOC00323
| PROSITE = PDOC00323
| CDD = cd14498
| PDB = {{PDB2|1d5r}}, {{PDB2|1i9s}}, {{PDB2|1i9t}}, {{PDB2|1j4x}}, {{PDB2|1m3g}}, {{PDB2|1mkp}}, {{PDB2|1ohc}}, {{PDB2|1ohd}}, {{PDB2|1ohe}}, {{PDB2|2c46}}
| PDB = {{PDB2|1d5r}}, {{PDB2|1i9s}}, {{PDB2|1i9t}}, {{PDB2|1j4x}}, {{PDB2|1m3g}}, {{PDB2|1mkp}}, {{PDB2|1ohc}}, {{PDB2|1ohd}}, {{PDB2|1ohe}}, {{PDB2|2c46}}
}}
}}
Line 118: Line 120:
{|
{|
|- valign=top
|- valign=top
|{{Pfam box
|{{Pfam box
|Symbol = Y_phosphatase2
|Symbol = Y_phosphatase2
|Name = Protein-tyrosine phosphatase, SIW14-like
|Name = Protein-tyrosine phosphatase, SIW14-like
| image = PDB 1xri EBI.jpg
| image = PDB 1xri EBI.jpg
| caption = Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana.<ref name="pmid18433060">{{cite journal |vauthors=Aceti DJ, Bitto E, Yakunin AF, etal |title=Structural and functional characterization of a novel phosphatase from the Arabidopsis thaliana gene locus At1g05000 |journal=Proteins |volume=73 |issue=1 |pages=241–53 |date=October 2008 |pmid=18433060 |doi=10.1002/prot.22041 |url=}}</ref>
| caption = Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana.<ref name="pmid18433060">{{cite journal |vauthors=Aceti DJ, Bitto E, Yakunin AF, etal |title=Structural and functional characterization of a novel phosphatase from the Arabidopsis thaliana gene locus At1g05000 |journal=Proteins |volume=73 |issue=1 |pages=241–53 |date=October 2008 |pmid=18433060 |doi=10.1002/prot.22041 |pmc=4437517 }}</ref>
|Pfam = PF03162
|Pfam = PF03162
|Pfam_clan = CL0031
|Pfam_clan = CL0031
|InterPro = IPR004861
|InterPro = IPR004861
|PROSITE =
|PROSITE =
|CDD = cd14528
|PDB = {{PDB2|1xri}}, {{PDB2|2q47}}
|PDB = {{PDB2|1xri}}, {{PDB2|2q47}}
}}
}}
|{{Pfam box
|{{Pfam box
|Symbol = PTPLA
|Symbol = PTPLA
|Name = Protein-tyrosine phosphatase-like, PTPLA
|Name = Protein-tyrosine phosphatase-like, PTPLA
|Pfam = PF04387
|Pfam = PF04387
|InterPro = IPR007482
|InterPro = IPR007482
|PROSITE =
|PROSITE =
|PDB = }}
|PDB = }}
|}
|}


==Expression pattern==
==Expression pattern==
Individual PTPs may be [[gene expression|expressed]] by all cell types, or their expression may be strictly [[tissue (biology)|tissue]]-specific. Most cells express 30% to 60% of all the PTPs, however [[hematopoietic]] and [[neuronal]] cells express a higher number of PTPs in comparison to other cell types. [[T cell]]s and [[B cell]]s of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, [[LYP]], [[SHP1]], [[CD45]], and [[HePTP]].<ref>{{cite journal |vauthors=Mustelin T, Vang T, Bottini N | title = Protein tyrosine phosphatases and the immune response | journal = Nat. Rev. Immunol. | year=2005 | volume=5 | issue=1 | pages=43–57 | pmid = 15630428 | doi = 10.1038/nri1530}}</ref> The expression of [[PTPN5]] is restricted to the brain. Differential expression of [[PTPN5]] is found in many brain regions, with no expression in the cerebellum.<ref name="pmid1714595">{{cite journal | vauthors = Lombroso PJ, Murdoch G, Lerner M | title = Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 16 | pages = 7242–6 | date = Aug 1991 | pmid = 1714595 | pmc = 52270 | doi = 10.1073/pnas.88.16.7242 }}</ref><ref>{{cite journal | vauthors = Bult A, Zhao F, Dirkx R, Sharma E, Lukacsi E, Solimena M, Naegele JR, Lombroso PJ | title = STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum | journal = The Journal of Neuroscience | volume = 16 | issue = 24 | pages = 7821–31 | date = Dec 1996 | pmid = 8987810 }}</ref><ref>{{cite journal | vauthors = Lombroso PJ, Naegele JR, Sharma E, Lerner M | title = A protein tyrosine phosphatase expressed within dopaminoceptive neurons of the basal ganglia and related structures | journal = The Journal of Neuroscience | volume = 13 | issue = 7 | pages = 3064–74 | date = Jul 1993 | pmid = 8331384 }}</ref>
Individual PTPs may be [[gene expression|expressed]] by all cell types, or their expression may be strictly [[tissue (biology)|tissue]]-specific. Most cells express 30% to 60% of all the PTPs, however [[hematopoietic]] and [[neuronal]] cells express a higher number of PTPs in comparison to other cell types. [[T cell]]s and [[B cell]]s of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, [[LYP]], [[SHP1]], [[CD45]], and [[HePTP]].<ref>{{cite journal |vauthors=Mustelin T, Vang T, Bottini N |year=2018 |title=Protein tyrosine phosphatases and the immune response |journal=Nat. Rev. Immunol. |volume=5 |issue=1 |pages=43–57 |doi=10.1038/nri1530 |pmid=15630428 |s2cid=20308090}}</ref> The expression of [[PTPN5]] is restricted to the brain, and differs between [[List of regions in the human brain|brain regions]], with no expression in the cerebellum.<ref name="pmid1714595">{{cite journal |vauthors=Lombroso PJ, Murdoch G, Lerner M |date=Aug 2021 |title=Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=88 |issue=16 |pages=7242–6 |bibcode=1991PNAS...88.7242L |doi=10.1073/pnas.88.16.7242 |pmc=52270 |pmid=1714595 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Bult A, Zhao F, Dirkx R, Sharma E, Lukacsi E, Solimena M, Naegele JR, Lombroso PJ |date=Dec 2021 |title=STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum |journal=The Journal of Neuroscience |volume=16 |issue=24 |pages=7821–31 |doi=10.1523/JNEUROSCI.16-24-07821.1996 |pmc=6579237 |pmid=8987810 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Lombroso PJ, Naegele JR, Sharma E, Lerner M |date=Jul 2021 |title=A protein tyrosine phosphatase expressed within dopaminoceptive neurons of the basal ganglia and related structures |journal=The Journal of Neuroscience |volume=13 |issue=7 |pages=3064–74 |doi=10.1523/JNEUROSCI.13-07-03064.1993 |pmc=6576687 |pmid=8331384 |doi-access=free}}</ref>


==References==
==References==
Line 148: Line 151:


==External links==
==External links==
*[http://www.med.monash.edu.au/biochem/research/projects/protein.html PTP Summary and Relevant Publications] at [[Monash University]]
* [http://www.med.monash.edu.au/biochem/research/projects/protein.html PTP Summary and Relevant Publications] at [[Monash University]]
* {{MeshName|Protein-Tyrosine-Phosphatase}}
* {{MeshName|Protein-Tyrosine-Phosphatase}}
* {{EC number|3.1.3.48}}
* {{EC number|3.1.3.48}}
Line 156: Line 159:
{{Esterases}}
{{Esterases}}
{{Enzymes}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
{{Portal bar|Biology|border=no}}


[[Category:EC 3.1.3]]
[[Category:EC 3.1.3]]

Latest revision as of 05:53, 3 June 2024

Protein-tyrosine-phosphatase
Protein tyrosine phosphatase 1, trimer, Human
Identifiers
EC no.3.1.3.48
CAS no.79747-53-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Search
PMCarticles
PubMedarticles
NCBIproteins

Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:

[a protein]-tyrosine phosphate + H2O = [a protein]-tyrosine + phosphate

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; EC 3.1.3.48) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.[1][2][3][4]

Functions

[edit]

Together with tyrosine kinases, PTPs regulate the phosphorylation state of many important signalling molecules, such as the MAP kinase family. PTPs are increasingly viewed as integral components of signal transduction cascades, despite less study and understanding compared to tyrosine kinases.

PTPs have been implicated in regulation of many cellular processes, including, but not limited to:

Classification

[edit]

By mechanism

[edit]

PTP activity can be found in four protein families.[6][7]

Links to all 107 members of the protein tyrosine phosphatase family can be found in the template at the bottom of this article.

Class I

[edit]

The class I PTPs, are the largest group of PTPs with 99 members, which can be further subdivided into

Dual-specificity phosphatases (dTyr and dSer/dThr) dual-specificity protein-tyrosine phosphatases. Ser/Thr and Tyr dual-specificity phosphatases are a group of enzymes with both Ser/Thr (EC 3.1.3.16) and tyrosine-specific protein phosphatase (EC 3.1.3.48) activity able to remove the serine/threonine or the tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes that have been phosphorylated under the action of a kinase. Dual-specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle.

LEOPARD syndrome, Noonan syndrome, and metachondromatosis are associated with PTPN11.

Elevated levels of activated PTPN5 negatively affects synaptic stability and plays a role in Alzheimer's disease,[3] Fragile X syndrome,[4] schizophrenia,[8] and Parkinson's disease.[9] Decreased levels of PTPN5 has been implicated in Huntington's disease,[10][11] brain ischemia,[12] alcohol use disorder,[13][14] and stress disorders.[15][16] Together these findings indicate that only at optimal levels of PTPN5 is synaptic function unimpaired.

Class II

[edit]

LMW (low-molecular-weight) phosphatases, or acid phosphatases, act on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates.[17][18]

The class II PTPs contain only one member, low-molecular-weight phosphotyrosine phosphatase (LMPTP).

Class III

[edit]

Cdc25 phosphatases (dTyr and/or dThr)

The Class III PTPs contains three members, CDC25 A, B, and C

Class IV

[edit]

These are members of the HAD fold and superfamily, and include phosphatases specific to pTyr and pSer/Thr as well as small molecule phosphatases and other enzymes.[19] The subfamily EYA (eyes absent) is believed to be pTyr-specific, and has four members in human, EYA1, EYA2, EYA3, and EYA4. This class has a distinct catalytic mechanism from the other three classes.[20]

By location

[edit]

Based on their cellular localization, PTPases are also classified as:

Common elements

[edit]

All PTPases, other than those of the EYA family, carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and possess a similar core structure made of a central parallel beta-sheet with flanking alpha-helices containing a beta-loop-alpha-loop that encompasses the PTP signature motif.[23] Functional diversity between PTPases is endowed by regulatory domains and subunits.

Low-molecular-weight phosphotyrosine protein phosphatase
Structure of a low-molecular-weight phosphotyrosine protein phosphatase.[24]
Identifiers
SymbolLMWPc
PfamPF01451
InterProIPR017867
SMARTSM00226
SCOP21phr / SCOPe / SUPFAM
CDDcd00115
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1bvh​, 1c0e​, 1d1p​, 1d1q​, 1d2a​, 1dg9​, 1jf8​, 1jfv​, 1jl3​, 1ljl​
Protein-tyrosine phosphatase
Structure of Yersinia protein tyrosine phosphatase.[25]
Identifiers
SymbolY_phosphatase
PfamPF00102
Pfam clanCL0031
InterProIPR000242
SMARTSM00194
PROSITEPS50055
SCOP21ypt / SCOPe / SUPFAM
CDDcd00047
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1a5y​, 1aax​, 1bzc​, 1bzh​, 1bzj​, 1c83​, 1c84​, 1c85​, 1c86​, 1c87​
Dual-specificity phosphatase, catalytic domain
Structure of the dual-specificity protein phosphatase VHR.[26]
Identifiers
SymbolDSPc
PfamPF00782
Pfam clanCL0031
InterProIPR000340
PROSITEPDOC00323
SCOP21vhr / SCOPe / SUPFAM
CDDcd14498
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1d5r​, 1i9s​, 1i9t​, 1j4x​, 1m3g​, 1mkp​, 1ohc​, 1ohd​, 1ohe​, 2c46​
Protein-tyrosine phosphatase, SIW14-like
Structure of a putative phosphoprotein phosphatase from Arabidopsis thaliana.[27]
Identifiers
SymbolY_phosphatase2
PfamPF03162
Pfam clanCL0031
InterProIPR004861
CDDcd14528
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1xri​, 2q47​
Protein-tyrosine phosphatase-like, PTPLA
Identifiers
SymbolPTPLA
PfamPF04387
InterProIPR007482
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Expression pattern

[edit]

Individual PTPs may be expressed by all cell types, or their expression may be strictly tissue-specific. Most cells express 30% to 60% of all the PTPs, however hematopoietic and neuronal cells express a higher number of PTPs in comparison to other cell types. T cells and B cells of hematopoietic origin express around 60 to 70 different PTPs. The expression of several PTPS is restricted to hematopoietic cells, for example, LYP, SHP1, CD45, and HePTP.[28] The expression of PTPN5 is restricted to the brain, and differs between brain regions, with no expression in the cerebellum.[29][30][31]

References

[edit]
  1. ^ Dixon JE, Denu JM (2018). "Protein tyrosine phosphatases: mechanisms of catalysis and regulation". Curr Opin Chem Biol. 2 (5): 633–41. doi:10.1016/S1367-5931(98)80095-1. PMID 9818190.
  2. ^ Paul S, Lombroso PJ (2020). "Receptor and nonreceptor protein tyrosine phosphatases in the nervous system". Cell. Mol. Life Sci. 60 (11): 2465–82. doi:10.1007/s00018-003-3123-7. PMC 11138652. PMID 14625689. S2CID 10827975.
  3. ^ a b Zhang Y, Kurup P, Xu J, Carty N, Fernandez SM, Nygaard HB, Pittenger C, Greengard P, Strittmatter SM, Nairn AC, Lombroso PJ (Nov 2018). "Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model". Proceedings of the National Academy of Sciences of the United States of America. 107 (44): 19014–9. Bibcode:2010PNAS..10719014Z. doi:10.1073/pnas.1013543107. PMC 2973892. PMID 20956308.
  4. ^ a b Goebel-Goody SM, Wilson-Wallis ED, Royston S, Tagliatela SM, Naegele JR, Lombroso PJ (Jul 2019). "Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model". Genes, Brain and Behavior. 11 (5): 586–600. doi:10.1111/j.1601-183X.2012.00781.x. PMC 3922131. PMID 22405502.
  5. ^ Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ (Apr 2022). "Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61". The Journal of Neuroscience. 30 (17): 5948–57. doi:10.1523/JNEUROSCI.0157-10.2010. PMC 2868326. PMID 20427654.
  6. ^ Sun JP, Zhang ZY, Wang WQ (2017). "An overview of the protein tyrosine phosphatase superfamily". Curr Top Med Chem. 3 (7): 739–48. doi:10.2174/1568026033452302. PMID 12678841.
  7. ^ Alonso A, Sasin J, et al. (2020). "Protein tyrosine phosphatases in the human genome". Cell. 117 (6): 699–711. doi:10.1016/j.cell.2004.05.018. PMID 15186772.
  8. ^ Carty NC, Xu J, Kurup P, Brouillette J, Goebel-Goody SM, Austin DR, Yuan P, Chen G, Correa PR, Haroutunian V, Pittenger C, Lombroso PJ (2021). "The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications". Translational Psychiatry. 2 (7): e137. doi:10.1038/tp.2012.63. PMC 3410627. PMID 22781170.
  9. ^ Kurup PK, Xu J, Videira RA, Ononenyi C, Baltazar G, Lombroso PJ, Nairn AC (Jan 2018). "STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease". Proceedings of the National Academy of Sciences of the United States of America. 112 (4): 1202–7. Bibcode:2015PNAS..112.1202K. doi:10.1073/pnas.1417423112. PMC 4313846. PMID 25583483.
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