Lecture 3 - growth factors and receptors Flashcards
why is receptor signal transduction impt?
- cell signalling required for cel-cell communication
- for cells to sense secreted signalling molecules (GFs) and respond
GFs - growth factors
PDGF
PDGF (platelet-derived growth factor):
- secreted by platelets to initiate wound healing process
- stimulates growth of fibroblast
fibroblast: forms much of the connective tissue
Mitogens
growth-stimulating factors able to induce proliferation.
eg. PDGF: attracts fibroblast into wound site and stimulates their proliferation
Src
Src is an oncoprotein - functions as a protein tyrosine kinase. It removes a high energy phosphate group from ATP and transfers it to a suitable protein substrate.
what is Akt/
PKB?
Akt/PKB (serine/threonine protein kinases) can phosphorylate multiple proteins within a cell
outcomes of Akt/PKB action?
- inhibit the anti proliferative actions of GSK-3b
- activate HIF-1a –> angiogenesis
- inhibit apoptotic function of BAD
- activate protein synthesis thorugh TSC2
GSK-3b: involved in energy metabolism, ER stress, inflammation…
HIF-1a: upregulating gene expression
BAD: cell death initiator
TSC2: modulate cell migration and invasiveness
significance
EGF receptor (EGFR)
- 1st growth factor discovered
- mitogenic effects
- suggests the existence of cell surface proteins that recognizes EGF
- growth factor binding to EGFR –> cell signalling
what is its structure?
EGFR
- ectodomain: ligand binding
- transmembrane domain: locates EGFR to the cell surface, rich in hydrophobic amino acids
- cytoplasmic domain: hgih homology to Src protein, activated upon binding of ligand to EGFR ectodomain, able to phosphorylate certain cytoplasmic proteins
relatioinship between oncoprotein and GFR
- EGFR closely related to v-ErbB (oncoprotein)
- the oncogene was originally discovered in avian erythroblastosis virus (AEV) which can transform RBC precursors to leukemia
- ErbB protein does not have an ectodomain (deletion)
since ErbB protein does not have an ectodomain, why would this deletion make it oncogenic?
- ErbB is constitutively active
- binding of ligand to ErbB ectodomain helps to regulate/slow down the rate of cell signalling
- deletion of ectodomain results in the lack of inhibition
mutation
deregulation of TRK receptor firing
- mutation affect receptor structure which can cause independent firing
- overexpression of receptors lead to more frequent collision of receptors leading to spontaneous dimerization of receptors and firing
cell signalling molecule
deregulation of receptor firing
- cancer cells acquire the ability to make a ligand for GFR they display on the cell surface (aufactor signalling amplificationtocrine signalling)
- this provides an alternative route for growth factor signalling amplification (compared to Ras/Myc)
using Ros and Fig gene as example
How does gene fusion causing constitutively dimerized receptors
- gene fusion –> formation of abnormal recombinant receptors (Ros fuse with Fig)
- Fig gene encodes protein that normally dimerizes spontaneously
- dimerization pulls 2 Ros receptor monomers together –> become constitutively active/ligand/signal independent
what is a common example of gene fusion causing constitutively expressed receptors (other than fig and ros)
Ret receptor fusing with other proteins.
contributes to papillary thyroid carcinomas
its main ligand: GFL
what are the receptors involved in cancer pathogenesis?
- cytokine receptor
- TGF-beta receptors
- notch receptor
- patched-smoothened signalling system
- cannonical Wnt signalling via frizzled receptors
- non-cannonical Wnt signalling via frizled receptors
- nuclear receptors
- integrin receptors
ctnpcnni
significance of cytokine receptors and some examples
- JAKs (Janus kinases) control development of hematopoietic cell types
- they dimerise and allow the molecule alpha-interferon to bind
- EPO receptor –> regulates development of RBC
- thrombopoietin (TPO) –> regulates development of blood platelets
- interleukin receptor –> regulate immune responses
significance of TGF-beta receptors and their examples
- function as a heterodimer
- type I and type II TGF-beta recepetors
- type II binds with TGF-beta protein –> activates type I by phosphorylation –>signal transduction
- TGF-beta receptors promote the acquisition of invasive properties in already transformed cells
significance and example of notch receptors
- has multiple ligands (NotchL, Delta, Jagged) which are immobilized cell surface proteins
- uses justacrine signalling
- composed of 2 parts, associated with non-covalent bonds
- binding of ligand to receptor –> endocytosis of ligand of the signal-emitting cell
significance and example of patched-smoothened signalling system
resting:
- Smoothened is inhibited by Patched. Activates the cleavage of Gli, cleaved part moves into the nucleus to operate as a transcription repressor.
Activation by hedgehog (Hh) signalling:
- ligand Hh binds to receptor Patched, activation of Smoothened such that it is released from the cytoplasmic vesicles. Smoothened move to surface of primary cilium and prevents the cleavage of Gli by unknown mechnisms
- Uncleaved Gli moves into nucleus and functions as activator
Smoothened (Smo): a cytoplasmic vesicle transmembrane protein
Patched: a transmembrane protein located on the CSM
Gli: transcriptional factors
Primary cilia: act as sensory organelles and transduction hubs
Significance of the cannonical Wnt signalling via frizzled receptors
Resting:
- no Wnt signal, no recruitment of dishevelled protein
- GSK-3beta is active and phosphorylates proliferation-promoting proteins eg. beta-catenin (tagging for degradation)
Wnt signalling:
- binding of Wnt ligand to frizzled and LRP receptor activates frizzled
- recruits dishevelled and axin protein –> inactivates GSK-3beta
- beta-catenin is not degraded, it accumulates in the cytoplasm and enters the nucleus to promote cell proliferation
GSK-3beta: glycogen synthase kinase-3beta
Significance of the non-cannonical Wnt signalling via frizzled receptors
- binding of Wnt ligand to Frizzled receptor stimulates alpha-subunit of the G-protein to release GDP and bind GTP.
- alpha subunit dissociates from the beta-gamma complex, both subunits can regulate downstream signalling cascade
GPCR significance in cancer development
most are not involved in cancer development
significance of nuclear receptors
- sense other classes of signalling ligands that have low Mr and are relatively hydrophobic
- leads to the activation of multiple nuclear DNA binding proteins that function as transcription factors and can directly regulate the expression of target genes
hydrophobic because it allows the ligands to penetrate the plasma membrane and go into the nucleus
Significance of integrin receptors
Normal cells:
- require binding to ECM and attachment to proliferate as contact loss result in apoptosis
- they can sense their attachment via integrin receptors which can bind to components of teh ECM
Transformed cells:
- can grow in anchorage-independent and proliferate without attachment
integrin receptors are specific
example of integrin
- Binding of ECM ligand to integrin ectodomain –> clustering of integrins to form focal adhesions
- affects cytoskeleton organisation
- formation of focal adhesions –> activate signalling pathways that evoke cell migration, proliferation and survival
