RTK signaling Flashcards
Class I receptors
such as the EGF receptor, have cysteine rich extracellular domains
Class II receptors
such as the insulin receptor, are similar to Class I except they are post-translationally cleaved into two subunits (alpha, beta) that are then crosslinked by disulphide bonds. The alpha-beta dimer is also disulphide crosslinked to for the active tetrameric receptor
Class III receptor
such as the PDGF receptor containing a variable number of immunoglobin-like domains. Their internal kinase domain may be split with the insert region containing a regulatory sequence that can be phosphorylated.
mechanism of activation for RTKs
RTKs are activated by ligand binding which via different potential mechanisms of dimerization brings the two internal kinase domains into close proximity. The kinase domains then phosphorylate each other in trans leading to full activation of the receptor.
name the protein-protein interacts that occur and lead to the activation of Ras for a named RTK
Epidermal GF causes dimerization of external ligands, bringing the teo internal Y kinases into juxtoposision. They Pi eachother on multiple Y residues. That pY residue is recognized by Grb2 (SH2+SH3 domains). Grb2 SH2 domain recognizes the pY and anything with this specific pattern; pYx asp x. SH3 domains recognize the polyproline-rich domains in Sos. Sos is GEFS. this stimulates Ras due to GDP being swapped for GTP, leading to Ras activation
Describe the structure of a named adapter protein that is involved in RTK signaling indicating how it interacts with other proteins
Adapter proteins such as Grb2 contain SH2 domains that allow them to bind phosphorylated tyrosine residues on RTKs in a sequence specific manner. They also contain SH3 domains (Grb2 has two) that allows it to bind poly-proline rich sequences on guanine nucleotide releasing proteins such as Sos.
Describe the mechanism of action for Ras activation and deactivation indicating what other proteins are potentially involved in regulating its activity
Ras is monomeric G-protein that when inactive has GDP bound. Upon activation it will exchange the GDP molecule for GTP rendering it able to activate proteins such as Raf. It’s activation is terminated by its intrinsic GTPase activity that converts the bound GTP to GDP. Ras activity is regulated by guanine nucleotide releasing proteins (GRNPs) that stimulated the exchange of GDP for GTP and GTPase activating protein (GAPs) that stimulated the GTPase activity.
What is the cellular function of the mitogen activated protein kinase (MAPK) cascade?
The MAPK pathway links activation of cell surface receptors to phosphorylation of transcription factors in the nucleus. The pathway allows prolonger signalling which is required for cells to proliferate/ differentiate
Why is Raf described as an integrator of cell signalling?
Raf is the first kinase in the MAPK pathway for it’s full activation it needs to be phosphorylated by a kinase such as protein kinase c (PKC) and bind Ras-GTP. As such it functions at the crossroads of GPCR signalling which activates kinase such as PKC and RTK signalling which activates RAS