Signal transduction

Question 1

What promotes ras activation GTP bound state? Inactive ras state?

Answer 1

SOS

GAP or GRP(coded by NF1)

Question 2

what is ras?

Answer 2

A membrane bound gtpase

Question 3

What kind of mutation results in ras mutation? What is the effect?

Answer 3

a single point mutation

Growth promotion and GTPase that doesn’t hydrolyze GTP

Question 4

What other raf independent pathways can ras activate?

Answer 4

PI3K, PLC

Question 5

Give example of raf mutation that causes cancer

Answer 5

BRAF, melanoma

Question 6

What other mutation can result in an always active RAS?

Why?

Answer 6

NF1 defective gene, has GTPAse activity.

Question 7

Wht disease is defective NF1 associated with? What kind of disease is it and what is it’s characteristics? WHy is restricted to certain cells?

Answer 7

neurofibromatosis
It is autosomal dominant, affect neural cres and forms benign tumours and glat pigmented lesions, associated with higher risk of malignancies.
Because maybe these cells the p120GTPASE is enough to compensate the lost function

Question 8

What are some ras directed therapies?

Answer 8

Farnesytrasnferase inhibitor
RAF inhibitor
EGFR inhibitor

Question 9

Give example of growth factor receptor targetting

Answer 9

HER2-herceptn used to treat breast cancer

IRESSA-tagets tyrosine kinase actovoty

Question 10

How do antibody targetting of TKR work?

Answer 10

AB binds to l2 internalizes it. Or can induce antibody dependent cell mediated cytotoxicity. They bind to cancer cells and then effector cellls will recognize and bind to it through FC receptor and then they lysate through cytotoxicity

Question 11

Herceptin works on both homodimers and heterodimers

Answer 11

false just homodimers

Question 12

Her3 doesn’t have intracellular activity just mediates her2 activation

Answer 12

true

Question 13

HER4 is associated with differentiation of tissue

Answer 13

True

Question 14

How is increased EGFR associated with metastasis

Answer 14

it increases cell motility, angiogenesis, proliferation

Question 15

How is it more effective to target EGFR and use radiotherapy as treatment?

Answer 15

It ceases cell cycle so the DNA can repair making it more sensitive to other types of therapies decreasing these consequences

Question 16

Why is it advantageous to use monoclonal antibody?

Answer 16

Because of the homology can target the different families and becuase it’s specific reduces toxicity.

Question 17

give an example of RTK inhibitor? Why is good?

Answer 17

Lapatinib-it acts nonspecificall can target EGFR anf HER2

Question 18

How are agents that target EGFR activity helpful?

Answer 18

It decreases signa; transduction by inhibiting phosphorylatio, increasing multiple antitumour activity and makes it more sesitive to chemo or radio therapy making it more effective

Question 19

Explain the CAMP pathway

Answer 19

ligand binds to GPCR activated and the heterotrimeric dissociates whne it is GTP bound, where alpha subunit will activate adenylate cyclase which will activate CAMP that will activate PKA that will activate transcription factors such as CREB which will bind to CRE in promoters and will activate enzymes that have to do with metabolism and other growth regulatory genes

Question 20

Can CAMP activate PLC?

Answer 20

Yes through the beta subunit

Question 21

Give an example of a non receptor protein kinase

Answer 21

JAK

Question 22

Outline the JAK activation and what it affects

Answer 22

JAK is activated when growth factor cytokine binds to receptor, the dimerize, oligomerize, are phosphorylated by JAK, STAT(TF) when phosphorylated will dissociate and dimerize and translocate to nucleus and transcribe genes that have to do with proliferation,immunity, apoptosis, differentiation

Question 23

JAk is the first step to cytokine mediated signalling

Answer 23

True

Question 24

How many members are there? And what are they activated by?

Answer 24

4, cytokines

Question 25

What other pathways can JAK activate?

Answer 25

PI3K, MAPK, it associates with GRB2 and SOS

Question 26

How can STAT be mutated to cause cancer?

Answer 26

Chromosomal translocation, 9 and 12 can cause ALL

Oncogenic transformation of src in TRK can activate STAT 3 all the time

Question 27

Explain the GSK-3 and IFN pathway

Answer 27

GSK3 activates proliferation and survival while IFN would cause the transcription of apoptotic genes by activating stat 1 instead of stat 5, this creates a negative feedback system

Question 28

Explain how the G-CSF and IFN gamma signalling can be plastic in cancer

Answer 28

Ifn gamma can instead activate stat 5 along with gcsf instead of stat 5 increasing proliferation and survival

Question 29

What are the 3 different proteins that are involved in signalling pathways and give examples

Answer 29

Adaptor proteins- GRB2
Docking protein-IRS1
scaffold proteins-KRS1

Question 30

Whats the difference?

Answer 30

adaptor-soulble protein with severla modular protein domain interaction
docking protein0several modular protein interaction sequesting signalling component near the receptor and mambrane
scafolding-mutivalent binding protein that hold members of transduction cascade together, that have non catalytic activity and just focuses enzyme activity in a certain area, or act as a molecular platform for signalling cascade,

Question 31

Explain the how MAPK pathway and IRS interact, how does it do this

Answer 31

PI3K activates map kinase by phosphorylating GRB2 and SH2 at low levels of ERK, this is possible because of teh mediating effect of GAB to synergetically activate erk through EGF and INS, a scaffolding protein called GAB, while MAOK suppresses PI3K at high ERK levels.

Question 32

Explain the regulation of EMT transition

Answer 32

RKIP would inhibit raf and this will not allow the expression of SNAIL and SLUG which are t.f that repress E-cadherin expression, however RKIP can be inhibited by SNAIL and MAPK if e-cadherin is expressed

Question 33

What are some other examples of gtpase involved in cancer? And what process is it involved with specifically?

Answer 33

Rho, rac involved in mitogenic signalling and metastasis