Biology 2382B Lecture Notes - Lecture 11: Gtpase, Sarcoma, Platelet-Derived Growth Factor

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Published on 17 Apr 2013
School
Western University
Department
Biology
Course
Biology 2382B
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Lecture 11: Receptor Tyrosine Kinases
Receptor Tyrosine Kinases (RTK)
Extracellular (ligand-binding) domain
Ligands include growth factors (NGF, PDGF, FGF, EGF) and insulin
Single transmembrane a-helix
Cytoplasmic domain with intrinsic tyrosine kinase activity which is stimulated by ligand binding
due to receptor dimerization
Adapter proteins are required
Ras acts as a GTPase switch protein to signal further “downstream” kinases
Aberrant signaling is at root of many human cancers
Activation of RTKs
odimerization allows for trans-
autophosphorylation of cytoplasmic
domains
ophosphotyrosines serve as docking
sites for downstream signal-
transduction proteins containing SH2
or PTB domains (adapter proteins).
oThe cytosolic domain of RTKs
contains a protein tyrosine kinase
catalytic site. In the absence of ligand
(1) the RTKs exist as monomers with
poorly active kinases. Ligand binding
causes a conformational change that
promotes formation of a functional dimeric receptor, brining together two poorly active kinases
that then phosphorylate each other on a tyrosine residue in the activation lip (2). Phosphorylation
causes the lip to moce out of the kinase catalytic site, thus allowing ATP or a protein substrate to
bind. The activated kinase then phosphorylates other tyrosine residues in the receptors cytosolic
domain (3). The resulting phosphotyrosines (PPT) function as docking sites for various ST
proteins
Adapter Proteins
- adapter proteins contain unique domains that
recognize specific sequences
- Common Adapter Proteins:
-SH2: src (sarcoma) homology 2 domain –
SH2 domains present in at least 100 human
proteins
-PTB: Phosphotyrosine binding domain
-IRS-1: Insulin receptor substrate protein
- Cytosolic proteins with SH2 or PTB
domains can bind to specific PPT residues in
activated RTKs or cytokine receptors. IN
some cases, these ST proteins then are
phophorylated by the receptors intrinsic or
associated protein tyrosine kinase,
enhancing their activity. Certain RTKs and
cytokine receptors utilize multi-docking
proteins such as IRS-1 to increase the
number of signalling proteins that are recruited and activated. Subsequent phosphorylation of a
receptor bound IRS 1 by the receptor kinase creates additional docking sites for SH2 containing
signalling domains.
Oncogenes

Document Summary

Ligands include growth factors (ngf, pdgf, fgf, egf) and insulin. Cytoplasmic domain with intrinsic tyrosine kinase activity which is stimulated by ligand binding due to receptor dimerization. Ras acts as a gtpase switch protein to signal further downstream kinases. Aberrant signaling is at root of many human cancers. Activation of rtks o o dimerization allows for trans- autophosphorylation of cytoplasmic domains phosphotyrosines serve as docking sites for downstream signal- transduction proteins containing sh2 or ptb domains (adapter proteins): the cytosolic domain of rtks. Adapter proteins contains a protein tyrosine kinase catalytic site. In the absence of ligand (1) the rtks exist as monomers with poorly active kinases. Ligand binding causes a conformational change that promotes formation of a functional dimeric receptor, brining together two poorly active kinases that then phosphorylate each other on a tyrosine residue in the activation lip (2).