Signal transduction Flashcards
What promotes ras activation GTP bound state? Inactive ras state?
SOS
GAP or GRP(coded by NF1)
what is ras?
A membrane bound gtpase
What kind of mutation results in ras mutation? What is the effect?
a single point mutation
Growth promotion and GTPase that doesn’t hydrolyze GTP
What other raf independent pathways can ras activate?
PI3K, PLC
Give example of raf mutation that causes cancer
BRAF, melanoma
What other mutation can result in an always active RAS?
Why?
NF1 defective gene, has GTPAse activity.
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?
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
What are some ras directed therapies?
Farnesytrasnferase inhibitor
RAF inhibitor
EGFR inhibitor
Give example of growth factor receptor targetting
HER2-herceptn used to treat breast cancer
IRESSA-tagets tyrosine kinase actovoty
How do antibody targetting of TKR work?
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
Herceptin works on both homodimers and heterodimers
false just homodimers
Her3 doesn’t have intracellular activity just mediates her2 activation
true
HER4 is associated with differentiation of tissue
True
How is increased EGFR associated with metastasis
it increases cell motility, angiogenesis, proliferation
How is it more effective to target EGFR and use radiotherapy as treatment?
It ceases cell cycle so the DNA can repair making it more sensitive to other types of therapies decreasing these consequences
Why is it advantageous to use monoclonal antibody?
Because of the homology can target the different families and becuase it’s specific reduces toxicity.
give an example of RTK inhibitor? Why is good?
Lapatinib-it acts nonspecificall can target EGFR anf HER2
How are agents that target EGFR activity helpful?
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
Explain the CAMP pathway
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
Can CAMP activate PLC?
Yes through the beta subunit
Give an example of a non receptor protein kinase
JAK
Outline the JAK activation and what it affects
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
JAk is the first step to cytokine mediated signalling
True
How many members are there? And what are they activated by?
4, cytokines
What other pathways can JAK activate?
PI3K, MAPK, it associates with GRB2 and SOS
How can STAT be mutated to cause cancer?
Chromosomal translocation, 9 and 12 can cause ALL
Oncogenic transformation of src in TRK can activate STAT 3 all the time
Explain the GSK-3 and IFN pathway
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
Explain how the G-CSF and IFN gamma signalling can be plastic in cancer
Ifn gamma can instead activate stat 5 along with gcsf instead of stat 5 increasing proliferation and survival
What are the 3 different proteins that are involved in signalling pathways and give examples
Adaptor proteins- GRB2
Docking protein-IRS1
scaffold proteins-KRS1
Whats the difference?
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,
Explain the how MAPK pathway and IRS interact, how does it do this
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.
Explain the regulation of EMT transition
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
What are some other examples of gtpase involved in cancer? And what process is it involved with specifically?
Rho, rac involved in mitogenic signalling and metastasis
