Lecture notes from Imperial College London, Medical Biosciences, 2nd year, Cancer Biology (CBIO) module
A crucial characteristic of every living cell is its ability to communicate with neighbouring cells. This interchange of information between a cell and its environment is what is known as cell...
Cell Signalling in Cancer
- cell signalling by membrane-bound receptors to allow neighbouring cells to communicate
=> response to environmental signals => preserve position & coordination of tissues
=> cell signalling pathways: regulate growth, proliferation, survival... -
What do the receptor tyrosine kinases look like?
- transmembrane p: 1) cytosolic (intracellular) region: RTK receptor tail which functions as a
tyrosine kinase 2) extracellular region: ligand binding site
- there are 20 RTK subfamilies with ≠ domains:
=> ErbB family:
=> receptors activated by epidermal GF
family (disulphide bonds determine specificity)
=> immunoglobulin-like domains
=> heparin-binding sites
=> glycosylation sites
=> EGFR (ErbB-1): mutated in cancers
=> ErbB2 act as a coreceptor for others
(HER2)
signalling proteins:
- cytosolic signalling p bind to docking sites
=> SH2 domain => bind the phospho tyrosine
(Y) on RTKs (affinity for specific aa seq)
=> bind simultaneously => several pathways
=> SH3 => bind & recruit to RTK p w/ proline
position of tyrosine
residues & unique docking Adaptor proteins: contain only SH3 and => bind receptor tail directly/ via adaptor p
sites (aa sequence) SH2 + lack catalytic domains (kinase, GAP, PLC...)
- signalling p propagate the GF signal => alter gene transcription
=> crosstalk bw ≠ intermediates in signalling pathways
- Shc (transforming p 1) & Grb2 (GF receptor-bound p 2): adaptor p for signal transduction/ cell com
- adaptor proteins link receptors to signalling pathway BUT don’t have an intrinsic signalling ability
, Mutations causing cancer affect signalling pathways
- aberrant signalling => escape normal control mechanisms => target for cancer chemotherapy
- oncogenic mutations of signalling p: overexpressed/ make abnormal p
=> include RTKs, EGFR, Ras, RAF, Akt, SRC, Abl, lipid kinases, estrogen receptor, Myc, cyclin..
=> deletions of tumour suppressors: p53, PTEN (negative regulator of the P13K-Akt pathway)
- RTKs: enzymatic activity in their polypeptide chain triggered by growth factors & some hormones
=> adjacent RTKs join with each other: cross-linked dimers produced locally in low conc
=> tyrosine kinase activity: cross-phosphorylation (RTK phospho tyrosine residues on the other)
④
P
membrane receptor
r cell sig.
1) receptiono
2) transduction
d
3) responseu(cellular activity,
activationc gene...)
e
Ras activation
-
d
- binding of a GF to an RTK => Ras activation l
o
=> membrane-bound GTP/ GDP-binding (G) protein => acts as a ‘molecular switch’
c
adaptor p Grb2 SH2 domain bindsa a
l 2
phosphotyrosine docking site and the
SH3 domains recuit Sos l
y
i
- Sos: guanine nucleotide exchange protein (GEF) n
=> GEF aids separation of GDP from Ras l
=> GTP spontaneously binds to Ras & GEF detaches o
=> GAP hydrolyses GTP to restore inactive GDP w
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