Flashcards in Lecture 10 - ras-Dependent Signaling Deck (59)
What is the connection between ras-dependent signaling and oncogenes?
A lot of retrovirus oncogenes have downstream ras-dependent signaling pathways
What are the 2 types of oncogenes?
1. v-src: oncogene in a retrovirus
2. c-src: native proto-oncogene in cell
What is a proto-oncogene? What does it code for?
Normal gene that could become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation.
What is a defective oncogenic virus?
Virus that has lost viral functions and takes advantage of an infection by helper viruses by infecting at the same time and inserting their genome into the helper virus package to propagate
What is Ras?
Monomeric super family of GTPases
What is the function of Ras?
Regulate cell growth through Ser/Thre protein kinases
What are the 5 subfamilies of Ras?
What is the function of Rho?
Reorganizes cytoskeleton through Ser/Thr protein kinases
2 other names for GTPase?
GTP binding protein = G protein
Compare the rate of the ras GTPase activity to that of the G alpha GTPase activity
Compare the rate of the ras GDP dissociation to that of the G alpha GDP dissociation
What % of cancers have activating mutations of c-ras?
How do ras GTPase make up for their slower rate of GTPase activity?
They recruit accessory proteins = GTPase activating proteins (GAPs)
What is the function of GAPs? How do they do it?
They markedly accelerate the intrinsic activity of c-ras by 10^4-10^5 by either activating the GTPase activity or accelerating GDP dissociation
What is the connection between GAPs and trimeric G proteins? What can we call this?
Trimer G proteins' substrates (eg: PLPC-beta) have GAP like activity resident on the G alpha subunit binding site so that when it binds, the substrate is activated but also it triggers the subunit to hydrolyze GTP
ANOTHER built-in OFF switch mechanism
What is the purpose of receptor tyrosine kinases recruiting GAPs to bind on phosphotyrosines?
These receptors are capable of inactivating ras by stimulating GTP hydrolysis
How is ras activated?
GDP dissociation + GTP binding
How is ras inactivated?
What proteins are responsible for activating ras? 3 names
How do they do this?
Guanine nucleotide exchange factor(GEF) = guanine nucleotide releasing protein (GNRP) = guanine nucleotide exchange protein (GNEP)
They markedly accelerate GDP dissociation
What are guanine nucleotide dissociation inhibitors (GDIs)?
They stabilize the c-ras-GDP state, stimulating c-ras inactivation
Inhibition of GAP: ras activation or inactivation?
Activation of GAP: ras activation or inactivation?
Inhibition of GEF: ras activation or inactivation?
Activation of GEF: ras activation or inactivation?
Inhibition of GDI: ras activation or inactivation?
Activation of GDI: ras activation or inactivation?
How is Rho activated/inactivated?
Same mechanisms as for Ras
Where are GEFs found? 2 places
1. Bound to receptor tyrosine kinases via a Grb-2 adaptor protein
2. In the nucleus
What controls if ras is activated or inactivated by receptor tyrosine kinases?
Whether GEFs or GAPs are recruited to bind to receptor tyrosine kinases