L4: Growth factor receptors part 2 Flashcards
PDGF receptor
tyrosine kinases receptors
There are two PDGF receptor subunits PDGFR-a and PDGFR-b.
The a chain binds to PDGF-A or PDGF-B or PDGF-C
The b-chain binds to PDGF-B or PDGF-D
PGF-BB known as the universal ligand.
PDGFR-aa was known as universal receptor
Bb can bind to any one of these receptors and alpha alpha can bind to any one of these isoforms apart from dd
Cells expressing universal receptor either shown bb or aa. Even tho same receptor isoform binding elicits diff results. Fine tuning within the system
PDGF receptor dimerisation
When gf binds to receptor it dimerises.
Receptors sitting in pm. When isoform dimers homo or hetero bring those 2 receptors together and grt activation in the tail phosphorylation of tyrosine. Recruits sh2
There are differences in the signalling downstream of PDGFR-a and PDGFR-b.
Thus the response of a call to PDGF depends on which of the two receptor types the cell expresses and which PDGF isoform binds to those subunits.
EGF family receptor signal
EGF family receptor signaEGFR First RTK to be characterised : EGF receptor sequencing by Waterfield’s lab revealed homology to v-erbB (one of two oncogenes carried by the avian erythroblastosis virus). v-erbB is a truncated form of the (chicken) EGFR gene (ErbB1)
EGFR/ErbB-1 is the prototype receptor tyrosine kinase.
EGF family receptors are expressed in almost all types of tissue
Four types
ErbB-1 (EGFR) - HER1
ErbB-2 - HER2 orphan receptor. no recognisable ligand.
ErbB-3 - HER3. no kinase activity. probably due to reg and control of the signalling pathway
ErbB-4- HER4
Very high homology with viral protein that can drive tumourgenesis. Viral protein was a truncated form of this egf receptor gene.
activation of receptor by EGF
EGF is a monomeric growth factor ligand so how is dimerisation of the receptor achieved?
EGF binds to two separate sites on the receptor
Binding of EGF changes the conformation of the receptor and allows dimerisation to occur.
2 egfs bind to bring 2 receptors together for dimerisation.
dimers
Dimers
Either homodimers or heterodimers are formed. The most common pairings are
homodimers of ErbB-1
ErbB-1/ErbB-4
ErbB-2/ErbB-3 ,
ErbB-2/ErbB-4
egfrb receptors
ligands have preference
ErbB1- EGF AREG, TGF-A
BTC, HBEGF, EREG- bind to 1 and 4
NRG1 AND NRG2- 3 and 4
NRG3 NRG4- 4
tgf-beta receptors
The receptors for the TGF-b super family of ligands have intrinsic serine/threonine kinase activity and are called receptor serine/threonine kinases (RSTKs)
The signalling pathways utilized by TGF-b family proteins are different than those for receptors with intrinsic tyrosine kinase activity or that associate with intracellular tyrosine kinases.
3 high affinity tgf-beta receptors
Once activated the TGF-b ligands regulate cellular processes by binding to three high-affinity cell surface receptors.
Type I TGF-b receptor (TbRI) : 53 kDa glycoprotein with an intracellular serine/threonine kinase domain
Type II TGF-b receptor(TbRII): 70-100 kDa glycoprotein with an intracellular serine/threonine kinase domain
Type III TGF-b receptor (TbRIII) : also known as betaglycan
280-330 kDa proteoglycan
tgf-beta receptor interaction
1a. TGF-b binds to TbRIII which present TGF-b to TbRII
1b. TGF-b binds to TbRII directly
Binding induces TbRII to recruit TbRI
TbRII then phosphorylates and activates TbRI
TbRI then phosphorylates intracellular proteins
When tgf-b binds to receptor 2 get recruitment of receptor 1. Through conf changes in these receptors. receptor 2 phosphorylates receptor 1 that actovates receptor phosphorylation? Brah idk my laptop didnt save my note.
PDGF and sis
PDGF and sis
sis, the oncogene of Simian sarcoma virus, was sequenced by Aaronson’s lab in 1983, but this initially provided no clues to function. Now known that sis is derived from the gene for the B chain of PDGF.
Cells transformed by sis secrete a functional PDGF (B:B homodimer).
ONLY transforms cells with PDGF receptors
Need gf and receptor to drive intracellular signalling
An example of inappropriate expression
If add virus and tasnform it and ot starts making bb isoform have closed loop where cell stimulates itself to constantly proliferate.
Pdgf receptor mutations in cancer
Sometimes amplification particulatly in alpha receptor that is more receptive to ligand binding.
More receptor on cell surface any ligand in vicinity triggers signalling, amplified response.
Point mutation: see alot on gastric intestinal tumours. Often means it doesnt need a ligand. Growth factor no longer needed to trigger the receptor. Constiutitve activation.
Translocation event: here receptor ended up inside cml cell. New fusion protein. Completely unreg. Tyrosine kinase. starts phospho tyrosine so get signalling that cant be controlled.
It is a kinase so can design small mol inhibitors that binds to that kinase and inactivate it so prevent phosphorylation of tyrosine. If prevent tyorsinekinase event block all of these downstream signalling. Can design inhibitors but problem is their kinase domains are very similar. Tyrosine kinases need to eb certain kind of shape, functionality, certain aa to phos that tyrosine. Lacks specificity.
look at image
egfr and disease
