Cell Surface Receptors: G-Protein-Coupled Receptors (GPCR)

CELL SURFACE RECEPTORS
G-protein-coupled receptors
(GPCR)
Enzyme-linked receptors
(Receptor tyrosine kinases)
Enzyme-coupled Cell Surface Receptors
Come back
SIGNALING THROUGH ENZYME-COUPLED RECEPTORS
Mutations in EGF pathways can lead to cancer.

Receptor Tyrosine Kinases (RTKs)
Extracellular domain
binds to ligand
Activated Receptor Tyrosine Kinases (RTKs) Phosphorylate
Themselves
EGF leads to dimerization and allows the

Two domains to phosphorylate each
other (mutual phosphorylation) . Leads
to conformational change and increased
SIGNALING THROUGH ENZYME-
COUPLED RECEPTORS
• Phosphorylated Tyrosines on RTKs Serve as
Docking Sites for Intracellular Signaling Proteins
Another example of
Mutual phosphorylation
Further
activation of
kinase
activity
Docking
sites
Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

RECEPTOR TYROSINE KINASE SIGNALING
Figure 15-54 Molecular Biology of the Cell (© Garland Science 2008)

Activated Receptor Tyrosine Kinases (RTKs) Phosphorylate
Themselves
Dimerization - Cross-phosphorylation
Proteins with SH2 Domains Bind to Phosphorylated Tyrosines
The labelled
Area is the
Binding pocket
Area to identify Not just tyrosine,

Specific Has to be
Amino acid phosphotyrosine
Domains to
Allow for
specificity
COUPLED RECEPTORS
• The GTPase Ras Mediates Signaling by Most RTKs
Downstream molecule of my tyrosine receptors, relays signal

The GTPase Ras Mediates Signaling by Most RTKs
or
n,
cer
te
The GTPase Ras Mediates Signaling by Most RTKs
EGEF leads to dimerization and cross phosphorylation

Will recruit protein called Grb2, with SH2 domain intera
SH3 domain interact with moelcule Ras-GEF, which inte
Off GDP to load GTP. GTP leads to conformation chang
COUPLED RECEPTORS
• Ras Activates a MAP Kinase Signaling Module
• MITOGEN-ACTIVATED PROTEIN KINASE

PATHWAY
Ras Activates a MAP Kinase Signaling Module
Map kinase kinase
Map kinase kinas
Amplification of signal,
Diversify functionality
Chro
Pho
Reg
gene
will
Two classes of proteins are phosphorylated
ENDOCYTOSIS OF EGF RECEPTORS
olic
he O
EG
pa
Th
so
st ca
pl
COUPLED RECEPTORS
• PI 3-Kinase Produces Lipid Docking Sites in the
Plasma Membrane
Create a docking site to recruit proteins.

PI 3-Kinase Produces Lipid Docking Sites in the Plasma Membrane
GCPR can lead to act

Which cleaves molec
COUPLED RECEPTORS
• The PI-3-Kinase–Akt Signaling Pathway Stimulates
Animal Cells to Survive and Grow
From lipid to protein kinase

The PI-3-Kinase–Akt Signaling Pathway Stimulates Animal Cells to
Survive and Grow
In the inner leaflet of membrane,

Enriched with PI(4,5)P2
Provides platform for protein
protein interaction
On different
membranes of
Different organelles,
Enriched with different
sets of PI’s,
Serves as landmark for
different organelles
Plasma membrane serves as platform for signaling molecules to interact wit

COUPLED RECEPTORS
• Some Enzyme-Coupled Receptors Associate with
Cytoplasmic Tyrosine Kinases.
Cytokine Receptors Activate the JAK–STAT Signaling Pathway

ds to
,
eins
re
Stat1 and Stat2 regulate
Target gene transcriptio
COUPLED RECEPTORS
• Signal Proteins of the TGFβ Superfamily Act
Through Receptor Serine/Threonine Kinases and
Smads
Signal Proteins of the TGFβ Superfamily Act Through Receptor
Serine/Threonine Kinases and Smads
Receptor is
not tyrosine
kinase,
Serine/threo
nine kinase.
Downstrem
molecule
is recruited
to TGFB
receptor.
Negative Feedback in Signaling
• NFκB signaling.
Many Stressful and Inflammatory Stimuli Act Through an NFκB-
Dependent Signaling Pathway
IkB forms complex with

NFkB. Phophorylation of
IkB to cause conformation
change. Ubquitylation
marks protein as garbage,
leads to degradation.
Liberation of NFkB leads
to trasncription event
This signal of NFkB leads

To production of IkBA, which
Binds back to NFkB to form comple
That constricts NFkB.
ALTERNATIVE SIGNALING ROUTES
IN GENE REGULATION
• Nuclear Receptors Are Ligand-Modulated
Transcription Regulators
Nuclear Receptors Are Ligand-Modulated Transcription
Regulators:
-Small, hydrophobic. Can readily cross the plasma membrane.

-Can also be intracellular metabolites.
Made from cholesterol

Nuclear Receptors Are Ligand-Modulated Transcription Regulators
Retinoic acid receptor

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CELL SURFACE RECEPTORS

Mutations in EGF pathways can lead to cancer.

EGF leads to dimerization and allows the

Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-54 Molecular Biology of the Cell (© Garland Science 2008)

Area to identify Not just tyrosine,

Downstream molecule of my tyrosine receptors, relays signal

EGEF leads to dimerization and cross phosphorylation

• MITOGEN-ACTIVATED PROTEIN KINASE

Map kinase kinase

Map kinase kinas

Create a docking site to recruit proteins.

GCPR can lead to act

From lipid to protein kinase

In the inner leaflet of membrane,

Plasma membrane serves as platform for signaling molecules to interact wit

Cytokine Receptors Activate the JAK–STAT Signaling Pathway

IkB forms complex with

This signal of NFkB leads

-Small, hydrophobic. Can readily cross the plasma membrane.

Made from cholesterol

Retinoic acid receptor

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