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INTRACELLULAR SIGNALLING II
JAK-STAT Pathway:
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§ Phoshotastes, such as SHP act upon the JAK-receptor complex and
desphosphorylate JAK
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SOCS bind to activated JAKs and inhibit catalytic activity
via a negative feedback loop
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TGFb is a serine/threonine kinase receptor but this signalling pathway differs from
the others at the level of the receptor
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Binding of TGF-b ligand to the type II receptor, which brings the type II and type I
receptors together, results in the phosphorylation of the type I receptor
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The latter, now activated, phosphorylates cytosolic Smad2 or Smad3 proteins (also
known as R-SMAD), and either of these phosphor-Smads then binds to Smad4 (also
known as co-SMAD)
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These target genes
include fibronectin, collagen type I etc
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R-SMAD-SMAD4 complexes often work in combination with different DNA-binding
cofactors, because SMAD complexes are sometimes not sufficient enough on their
own to upregulate transcription
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§ TFs such as AP-1
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MAP kinase family members were originally identified from studies of mutated
proteins in aggressive cancers
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For example, Ras is mutated in 30% of all human cancers and Raf is mutated in 60%
of malignant melanomas
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Microinjection of antibodies to Ras protein:
§ Blocks the stimulation of DNA synthesis by serum or PDGF + EGF
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Blocks transformation by v-src – this is because Ras function has been shown
to be necessary for v-Src transformation of human epithelial cells
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It’s been found that the
signalling cascade lying downstream of Raf may be strongly activated without
any direct involvement of Ras
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Transformation of cells by c-Src is not blocked by inhibition of the Ras-MAPK
pathway at the level of Ras or MEK or by inhibition of the PI3K pathway
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However, when both pathways are simultaneously inhibited, transformation is
blocked
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Mutations in Ras:
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V600E Mutation:
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That is, the level of the protein has not
changed but simply the overall activity of the protein
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MAPK signalling to cell cycle control depends on both receptor and integrin
signalling
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This allows us to place PAK downstream of Ras
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We know that Raf and MEK phosphorylation lead to proliferation via Erk, but
increased Raf and MEK phosphorylation might also lead to migration through Erk
activity in the cytoplasm
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Therefore, Erk increases cell proliferation and cell migration, and therefore
mutations in this protein lead to cell invasion – metastasis
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STATs is activated downstream of c-Src in some cell types
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SMADs and Cancer:
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Targets for Controlling Disease:
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§ Vemurafenib can promote wild-type raf dimers
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Cancer cells become re-activated via stromal cell secretion of hepatocyte
growth factor (HGF)
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Currently, compound 12 is a suggested drug that could potentially block the Raseffector interaction and thus inhibit Ras action altogether