Receptor TYROSINE kinases (some recap) Flashcards
What basic mechanism is used by receptor kinases (serine threonine or tyrosine)
Dimerization
What type of receptor would induce a SMAD signaling pathway?
TGFbR
Briefly describe the SMAD signaling pathway
(NOT TYROSINE KINASE) TGFb binds as a dimer to heterodimeric receptor.
Type 2 receptor phosphorylates Type 1 receptor (serine residue)
Type 1 receptor phosphorylates and activates SMAD2.
SMAD2 binds further SMAD, SMAD4.
Exposing NLS, go to nucleus and be Transcription factor
How is SMAD signaling turned off?
SMAD3/4 complex has gene product = SMURF (smad ubiquitination complex)
also phosphatase for SMAD (signal is technically ratio of phosphorylated to unphosphorylated smad)
Briefly describe JAK STAT signaling pathway
Cytokine binds 2 identical monomers on membrane. = dimerization
Dimerisation brings tog the two associated kinase domains (JAKs)
JAKs crossphosphorylate = activated
Activated JAK phosphorylates intracellular domain of receptor
SH2 domain on STAT (transcription factor) recognises phosphorylated-tyrosine on receptor and binds.
JAK phosphorylates STAT (SH2 domain)
Phosphorylated STAT recognises second phosphorylated STAT (via p-tyr) and dimerise
Dimerised STATs have intact NLS and go to nucleus to act as a TF
What is an example of a ligand that would induce the JAK STAT signaling pathway?
Growth hormone
How is JAK STAT signaling turned off?
SOCS has SH2 domain (is ubiquitin ligase)
Phosphatase also has SH2 domain
What does a PTB domain in an adaptor protein recognise?
Recognises phosphorylated tyrosine residues (similar to SH2 domain but recognises 3 residues before the P-tyr)
What does an SH3 domain recognise?
polyproline
Where does the specificity of tyrosine kinase pathways come from?
The specificity of tyrosine kinase pathways comes from the adaptor proteins (eg SH2 domains etc) NOT from the kinase itself
What are SH2 domains generally like?
Small and have their N and C termini close together at opposite sides of the binding site
What is the adaptor protein for VEGF pathway?
Grb2
What type of molecule is VEGF
VEGF is a dimer
What type of receptor is VEGFR
Single pass receptor tyrosine kinase
Briefly describe VEGF signaling pathway
VEGF binds VEGFR receptor monomers to bring them together.
Both monomers have intracellular low acting kinases.
Dimerization of monomers allows kinase domains to cross-phosphorylate.
Phosphorylated tyrosine residues on kinase domains of receptor are recognised by SH2 domain of Grb2
This reveals 2 SH3 domains on Grb2 which bind polyproline rich sequence in SOS protein bringing it to membrane
What type of protein is SOS?
SOS is a GEF (for RAS)
What does VEGF stand for?
Vascular endothelial growth factor
What is the function of a GEF?
GEF = guanine exchange factor. Encourages dissociation of GDP from a GTPase and exchange with GTP
What is the function of a GAP?
GTPase activating protein - encourages the hydrolysis of GTP - GDP in GTPases.
What type of gene is the gene for RAS GTPase?
An oncogene - mutated RAS proteins are found in cancers (hydrolysis rate too slow and switch is left active for too long)
How does RAS act as an effective switch?
When RAS binds GTP it forms a network of hydrogen bonds that fold two loops of the protein in towards GTP (switch 1 and switch 2). When GTP is hydrolysed these two switches spring out. This conformational change allows RAS to function as a switch.
Which residue is commonly mutated in cancerous RAS proteins?
Gly12
What is the RAS kinase cascade?
RAS - RAF - MEK - ERK
What two states can ERK exist in?
ERK can either be transported out of Nucleus (via NES) or transported into nucleus (Via NLS)
