Intro to RTK's Flashcards
Common domains in all RTKs
EC ligand binding domain
A single TM helix
Cytoplasmic domain that has the kinase, C-terminus, and the juxtamembrane regulatory regions.
Factor in dimerisation of insulin and IGF1receptors
They form disulphide linked dimers
EGFR dimerisation
HER2 monomer has no known ligand, with its dimerisation domain exposed in its resting state.
HER3 has no active kinase domain.
Can form EGFR homodimer, HER2/EGFR dimer. HER2 homodimer, HER2/HER3 dimer (neurkgulin-1), and HER2/HER4 dimer (neurkgulin 1-4)
PDGF dimerisation, ligands and functions
There are 4 different PDGF ligands: -A, -B, -C, and -D. They form homodimers, except for PDGF-AB.
There are 3 PDGFR dimers (from two PDGFR isoforms): aa (binds AA, AB, BB, and CC ligands), aB (binds AB, BB, CC, and DD ligands), and BB (binds BB and DD ligands)
where a=alpha, B=beta
stabilises endothelial tubes during development, promotes endothelial cell proliferation, and induces blood vessel growth. Furthermore, PDGFR-B is found in pericytes, playing an important role in recruitment of pericytes during angiogenesis and wound healing.
VEGFRs dimerisation, roles and ligands
4 ligands: -B, -A, -C, and -D.
3 VEGFRs: 1 (binds A and B ligands), 2 (binds A, C, and D ligands), 3 (binds C and D ligands)
VEGFR1 regulates monocyte and macrophage migration
VEGFR2 regulates cardiovascular, haematopoietic and lymphatic development. Angiogenic.
VEGFR3 regulates lymphanogiogenesis.
Examples of cross RTK family interactions and co-receptors
PDGF and VEGF ligands can interact with PDGFR-a, PDGFR-B, and VEGFR2s.
NRP-1 (neuropilin-1), a VEGF co-receptor, can bind to PDGF-DD at the same time as PDGFR-B, mediating pericyte recruitment to endothelial cells in injury, or angiogenesis,
Further examples of RTK dimerisation, and the effect of growth factors on their EC domains
in TrkA, NGF dimers (a dimerised ligand) connects the two TrkA monomers. TrkA do not interact directly with each other, NGF mediates their connection.
In KIT, a stem cell factor initiates the dimerisation. Upon this, two Ig domains (D4 + D5) reorientate.
In FGFR, the two monomers contact each other through their D2 Ig domains. Here 2 heparin sulphate proteoglycans (HSPG).
Role of proteoglycans in RTK signalling and example
They can trap growth factors in the EC matrix and then deliver them to neighbouring proteins.
E.g., HGF to MET
Eph/EPHRIN signalling overview and mechanisms
Eph proteins are the largest RTK family. Roles in bone homeostasis, immunity, and cancer. Receptor isoforms are EphA and EphB.
The ligands for the Eph receptors are membrane bound, being attached by a glycosyl phosphatidylinositol anchor called EPHRIN-A, or a single TM domain called EPHRIN-B.
The interactions between ligand and receptor occur at cell-cell junctions. 2 cells - one with ligand, one with receptor.
Features of RTK activation and some specific examples
They all have N- and C-lobes.
In the FGFR and insulin receptors, the activation loop directly interacts with the active site of the kinase, blocking the protein substrates, ATP, or both. These autoinhibiory interactions are ceased following ligand binding and phosphorylation of tyrosine.
In KIT and the PDGFRs the juxtamembrane region interact with elements of the active site to stabilise an inactive conformation. Phosphorylation of Tyr allows the kinase to adopt an active conformation.
Allosteric activation occurs in the EGFR TKD. Occurs by contact between the C-lobe of one TKD with the N-lobe of another TKD. The activator TKD destabilises the auto inhibitory interactions.
EGFR signalling and role of SH2 and SH3 domains in RTK signalling
EGFR signals through PI3K, PLCy, and the Ras-Raf-MEK-MAPK pathways to alter gene expression.
Interactions between phosphotyrosine and SH2 in Grb2 mediate downstream signalling through the MAPK pathway. SH3 domain in Grb2 medates Ras signalling that then downstream activates MAPK.
