Lecture 10 - ras-Dependent Signaling Flashcards Preview

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Flashcards in Lecture 10 - ras-Dependent Signaling Deck (59)
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1

What is the connection between ras-dependent signaling and oncogenes?

A lot of retrovirus oncogenes have downstream ras-dependent signaling pathways

2

What are the 2 types of oncogenes?

1. v-src: oncogene in a retrovirus
2. c-src: native proto-oncogene in cell

3

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.

4

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

5

What is Ras?

Monomeric super family of GTPases

6

What is the function of Ras?

Regulate cell growth through Ser/Thre protein kinases

7

What are the 5 subfamilies of Ras?

1. Ras
2. Rho
3. Arf
4. Rab
5. Ran

8

What is the function of Rho?

Reorganizes cytoskeleton through Ser/Thr protein kinases

9

2 other names for GTPase?

GTP binding protein = G protein

10

Compare the rate of the ras GTPase activity to that of the G alpha GTPase activity

Slower

11

Compare the rate of the ras GDP dissociation to that of the G alpha GDP dissociation

Same

12

What % of cancers have activating mutations of c-ras?

30%

13

How do ras GTPase make up for their slower rate of GTPase activity?

They recruit accessory proteins = GTPase activating proteins (GAPs)

14

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

15

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

16

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

17

How is ras activated?

GDP dissociation + GTP binding

18

How is ras inactivated?

GTP hydrolysis

19

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

20

What are guanine nucleotide dissociation inhibitors (GDIs)?

They stabilize the c-ras-GDP state, stimulating c-ras inactivation

21

Inhibition of GAP: ras activation or inactivation?

Activation

22

Activation of GAP: ras activation or inactivation?

Inactivation

23

Inhibition of GEF: ras activation or inactivation?

Inactivation

24

Activation of GEF: ras activation or inactivation?

Activation

25

Inhibition of GDI: ras activation or inactivation?

Activation

26

Activation of GDI: ras activation or inactivation?

Inactivation

27

How is Rho activated/inactivated?

Same mechanisms as for Ras

28

Where are GEFs found? 2 places

1. Bound to receptor tyrosine kinases via a Grb-2 adaptor protein
2. In the nucleus

29

What controls if ras is activated or inactivated by receptor tyrosine kinases?

Whether GEFs or GAPs are recruited to bind to receptor tyrosine kinases

30

Once activated, what does ras do?

Induces the MAP-kinase cascade