14th Feb - WNT, NFkB, Hedgehog and notch signalling pathways Flashcards
Where are notch ligands localised?
They are membrane bound
What are the notch receptors?
JAG1/JAG2, DLL1/DLL4, DLL3
Outline the notch signalling pathway
Notch binds notch ligands
Notch is cleave within its ectodomain
Cleaved notch is free in the cytoplasm
Notch migrates to the nucleus where it displaces Co-R w/ a CoA therefore activating the TF CSL –> gene expression
What are the targets of NOTCH signalling?
c-myc
NRARP –> Wnt signalling
HES and HEY genes represses the differentiation process
What are the main functions of NOTCH signalling ?
Cell-cell communcation causing lateral inhibition, lateral induction, stem cell maintenance or stem cell differentiation
How is the NOTCH ligand regulated?
Neuralized - internalisation and degradation of delta like
Fringe - block/promote the formation of the DSL ligand-Notch receptor pairs. Act in the golgi apparatus to transfer G1cNAc to the extracellular domain of Notch
Deltex1 - a positive regulator of Notch signaling through protein-protein interactions
How is the active intracellular domain of NOTCH generated?
ADAM 10, 17 - cleaves the ectodomain
Gamma-secretase - TM domain cleavage
NUMB - antagonizes NOTCH signaling by ubiquitination of membrane bound Notch 1 receptor and its subsequent degradation following receptor activation
How is the NOTCH ICD deactivated?
Cyclinc/Cdk8 phosphorylate the NOTCH ICD
Fbw/Sel10 ubiquitinates NOTCH ICD –> disassembly of the activator complex
Does the NOTCH signalling pathway promote/suppress oncogenesis?
It can do either depending upon the context
Outline the Wnt signalling pathway
Wnt binds to the frizzled receptor, activating dishevelled, which inhibits the GSK3-APC-Axin complex, leading the the release of Beta catenin –> TCF activation –> Myc, CycD and Axin 2 expression
Vivian (2012) opposes the current model of Wnt signalling, what do they propose instead?
Wnt signaling suppresses Beta-catenin ubiquitination –> complex saturation by accumulated phospho beta catenin therfore there is more free cytosolic beta catenin
What is familial adenomatous polyposis (FAP)?
A familial disorder in which patients develop multiple polyps of the colon, which usually give rise to tumours over time
What germline mutation causes FAP?
A mutation in the adenomatous polyposis coli (APC) gene, a known tumour suppressor
What are the classical direct mammalian targets of Beta-catenin?
cyclin D1 and c-myc
How does Beta-catenin OE affect cell-cell adhesion?
Beta catenin OE –> e-cadherin de-regulation –> increase in cell motility and decrease in cell anchorage
Outline the NFkB pathway
Stimuli activate IkB kinase (IKK)
IKK phosphorylates the inhibitor of kB (IKB) which inhibits NFkB
IkB phosphorylation labels it for proteasomal degradation releasing NFkB
NFkB translocates to the nucleus where it acts as a transcriptional activator
What are the two most common subunits of NFkB?
p50 and p65
Which type of cancer is the NFkB pathway most prominent in?
p50 and p65
What are the key physiological responses elicited by the NFkB pathway?
Cell survival Immune response/inflammation Adhesion/invasion/metastasis angiogenesis proliferation
Outline the hedgehog signalling pathway
Hedgehog binds to patched
Patched moves away from smoothened therefore activating it
Smoothened activates Gli1
Gli1 translocates to the nucleus and acts as a transcriptional activator
What are the three main mechanisms that hedgehog signalling promotes cancer
Smoothened activation mutation
Patched loss of function mutation
Hedgehog autocrine signalling
What drug can be used to target the smoothened receptor?
Cyclopamine
