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Biology 2382B Lecture Notes - Trastuzumab, Chromosome, Chemotherapy

Course Code
BIOL 2382B
Jessica Kelly

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Lecture 17 Receptor Tyrosine Kinases (RTK)
Receptor Tyrosine Kinases (RTKs)
N-terminal Extracellular (ligand-binding) domain
o Ligands include growth factors (i.e. NGF, PDGF, FGF, EGF) and insulin
(in some cases) which trigger cell growth, proliferation, & differentiation
Single transmembrane a-helix (unlike multi-membrane spanning GPCR’s)
C-terminal cytoplasmic domain with intrinsic tyrosine kinase activity which is
stimulated by ligand binding binding causes receptor dimerization
Receptor dimerization results in autophosphorylation which activates kinase
activity other tyrosine residues in cytosolic domain are also phosphorylated
Tyrosine phosphorylation recruits adaptor proteins that mediate interactions
with Ras
Ras acts as a GTPase switch protein to signal further “downstream” kinases
Aberrant signaling inovled in many types of human cancers
These receptor proteins are involved in signalling pathways that result in cell growth
proliferation, and differentiation…thus disruptions in these signalling pathways often
result in cancer & are therefore a key interest of studying in cellular signalling…

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Activation of RTKs
RTK’s usually exist monomerically when not bound to their respective ligand
(growth factor)
Ligand Binding
causes dimerization of monomeric RTK’s by causing a
conformational change in the receptor
Dimerization results in activation of the cytosolic portion of the protein
activates intrinsic kinase activity of the protein (RTK)
= trans-autophosphorylation of cytoplasmic domains (tyrosine’s)
Initial phosphorylation on the activation lip (key event)
o Acts a trigger to increase kinase activity
o RTK phosphorylates tyrosine residues on other portions of the
cytoplasmic domain
Phosphotyrosines serve as docking sites for downstream signal-transduction
proteins containing SH2 or PTB domains (adapter proteins)…

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Adapter Proteins
Phosphotyrosine residues recruit specific adapter proteins (often specificity
provided by specific residues adjacent to the phosphotyrosine)
Adapter proteins have SH2 domains that recognize phosphotyrosines
PTB domains also specifically bind to phosphotyrosine residues
SH2 and PTB domains essential for recognition of the RTK by adapter
Adapter proteins act to mediate interactions between RTK and other signalling proteins
(i.e. Ras)
Phosphorylation of adapter proteins by RTK can act to recruit others results
in the signal being transmitted
Adapter proteins contains unique domains
that recognize specific sequences…
Common Adapter Domains:
o SH2 -src homology 2 domain
(Src is an acronym for sarcoma)
o PTB Phosphotyrosine-binding
IRS-1- Insulin receptor substrate protein
SH2 domains present in at least 100
human proteins…many of which are
signalling proteins…
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