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cell signalling lecture 3 (How do receptors tyrosine kinases receptors…
cell signalling lecture 3
What types of enzyme coupled receptor are there?
receptor tyrosine kinases
autophosphorylates specific tyrosines
receptor serine/threonine kinases
autophosphorylates specific serines or threonines
tyrosine-kinase-associated receptors
no intrinsic enzymatic activity
directly recruit cytoplasmic tyrosine kinases
causes a conformation change resulting in activation of kinase domain
How do receptors tyrosine kinases receptors work?
receptor dimerisation
autophosphorylation
signal protein binding
this activates intracellular signaling proteins
this activates the activity of the RTK
reversing of the signal
phosphatase activity
receptor internalisation and degradation
examples
Ras activation
adaptor protein binds to RTK
Ras-GEF binds to adaptor protein
Ras-GEF phosphorylates GDP to GTP --> activation
Ras then stimulates a serine threonine/kinase cascade
MAPKKK --> MAPKK --> MAPK
changes in protein activity
changes in gene expression
MAP = Mitogen-activated kinases
(signalling switch)
Importance
central to cell cycle control
the ras ene is mutated in 30% of all human cancers
Ras and other members of the pathway are proto-oncogenes and tumour suppressors
PI3K activation
phosphorylation of IP3
activation of protein kinase
phosphorylation of Akt
Akt then phosphorylates downstream proteins
promotes cell survival
downstream proteins inhibit apoptosis
examples of RTK signalling molecules
Epidermal growth factor
receptor:
EGF receptor
Responses
stimulates cell survival
growth
proliferation
differentiation
Insulin
receptor
insulin receptor
responses
stimulates utilisaiton of carbohydrate
protein synthesis
Vascular Endothelial Growth Factor
Receptor
VEGF receptor
responses
stimulates angiogenesis
Signal cross-talk
integration of information from many different signalling pathways to initate an appropriate response
example
signal A B stimulate kinase 1
signal B D stimulate kinase 2
signal C inhibit kinase 1 and 2