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Lecture 9

Biology 2382B Lecture Notes - Lecture 9: Rous Sarcoma Virus, Insulin Receptor Substrate, Transmembrane Domain


Department
Biology
Course Code
BIOL 2382B
Professor
Sashko Damjanovski
Lecture
9

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Lecture 9: Receptor Tyrosine Kinases (RTKs)
Receptor Tyrosine Kinases (RTKs) have three domains:
oExtracellular domain which binds ligands.
oTransmembrane domain with a single alpha-helix
oCytoplasmic domain that has intrinsic/autophosphorylation tyrosine kinase activity which is activated
by ligand binding and leads to receptor dimerization (which causes trans-autophosphorylation).
After the RTK has dimerized and self-phosphorylated its tyrosines, adapter proteins are required to activate Ras,
a GTPase which signals further “downstream” kinases.
oSignalling that is done wrong is the root cause of many human cancers
RTK Activation. First, two ligands must bind to two separate receptors. Once this occurs, the receptors can
dimerize, creating an active tyrosine kinase domain in the cytosolic region.
oTrans-autophosphorylation occurs where the
active tyrosine kinase domain can take ATP
and phosphorylate the opposite protein at
their tyrosine. The opposite protein will
reciprocate with phosphorylation.
oPhosphorylation initially occurs on the
tyrosines of the activation lip (i.e. it is the
first place to be phosphorylated). After the lip
tyrosines are phosphorylated, the other
tyrosines in the cytosolic domain are
phosphorylated as well.
Different RTKs will have different number of tyrosines they require to be phosphorylated.
oThe phosphotyrosines (phosphorylated-tyrosines) act as “docking sites” for adapter proteins that
contain SH2 or PTB domains.
Adapter Proteins
Adapter proteins contain unique domains that recognize specific sequences on RTKs in order to transmit the
signal to RAS. Common adapter protein domains are the following:
oSH2 (src homology 2 domain), where src is an acronym for sarcoma.
Similar to SH3 domain.
There are SH2 domains present in at least 100 human
proteins.
oPTB (phosphotyrosines-binding domain). These are found on multi-
docking proteins (i.e. proteins which can act as a dock for other
signal transduction proteins).
IRS-1 (Insulin receptor substrate protein) contains a PTB domain.
Discovery of the First Oncogene
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