Lecture 3: Sustained proliferative signaling I Flashcards
consequences of phosphorylation by CyclinD/CDK4,6 complex
inactivation of RB1 gene (which is a tumor suppressor), complex launches S-phase once the hyperphosphorylation of substrate reaches a critical threshold
how do wounds trigger blood clotting?
- activated platelets precipitate blood cells, and release the content of their a-granules
- the liquid phase (serum) contains factors such as PDGF that activate and attract fibroblasts to initiate wound healing
de quoi est composé le sang?
blood clot (platelets) and serum containing platelet-derived growth factor (PDGF)
what does healthy growth typically relies on? (stimulated by PDGF and EGF)
paracrine growth factors, to reduce the risk of uncontrolled cancerous tissue growth
different modes of growth factor signaling
autocrine (the same cell produces the factor and has the receptor), juxtacrine (cells are connected with gap junctions) and paracrine (cells are close, local signaling)
what is v-Src?
gene found in RSV (virus) that is responsible for its tumorigenicity in chickens
why is v-Src a viral oncogene?
it is sufficient to induce many features of a full blown tumor in cultured cells:
- cell shapes changes
- loss of ‘contact inhibition’
- anchorage.independent survival & growth
diff between EGF-R and vErbB
vErbB lacks an inhibitory extracellular domain
diff oncogenic mutations of RTK
hypersensitive to ligands, independent of ligands and overexpression of RTK
what causes overexpression of RTKs?
gene amplification
types of mutations of RTK
extracellular domain and kinase domain
type de thérapies pour les cancers liés au RTKs
drugs = ATP analogs that block RTK activity
role of the multiple p-tyr residues on PDGF-beta and EGF receptors
these are docking sites for multiple proteins, opportunities to modulate signal transduction
What are SH domains and what are their functions?
Src homology domains share sequence similarity with non-catalytic domains of the cytoplasmic tyrosine kinase Src; they are adaptors
what characterizes the growth of “transformed” cells?
shape changes; anchorage-independence; loss of contact inhibition
epistatic def
mutations in one of them can hide the phenotype effect of mutations in one of the others
gain-of-function mutation def
increased or prolonged activity compared to wild-type
example of factor recruited by p-EGFR
Son-of-sevenless (Sos) which activates Ras; it is a GEF
what is Ras?
membrane-anchored small GTPase
how is Ras switched off?
when it binds GTPase-activating protein (GAP)
% of human tumors in which activating mutation in Ras are found
20-25%
2 kinds of oncogenic mutations in Ras
Gly12 and Gln61 which usually interact with GTP can be mutated to block GTP hydrolysis
what is KRAS G12C mutation?
mutation of the pro-oncogene KRAS which blocks the protein in the activated mode, leading to uncontrolled proliferation -> tumor
frequency of KRAS G12C mutation
found in 13% of Non-Small Cell Lung Cancer
active Ras binds and stimulates at least 3 effectors: ils permettent de faire quoi?
- PI3K/Akt pathway leads to growth, proliferation and survival
- RAF/MEK/ERK pathways leads to transcription and protein synthesis
- Ral-GEF pathways leads to motility
que fait le Ras-activated PI3K ?
it activates the phospholipid PIP2 -> PIP3, and PIP3 allows membrane docking of PH-domain proteins
effects of AKt/PKB
promotes survival, proliferation and cell growth by inhibiting or activating substrates
what are PH-domain proteins?
Pleckstrin Homology domains that bind to PIP3 with high affinity
