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GROWTH FACTORS II
Extracellular Signal Molecules:
The positively acting signal proteins that influence cell survival, cell growth,
and cell division can be classified, on the basis of their function, into 3 major
categories:
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Signal Transduction:
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Receptors have both an intracellular and extracellular space
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Binding of the messenger molecule or ligand initiates a signalling
cascade
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• Conversion of phospholipids
• Protein:protein interactions
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Once a ligand has activated a receptor, signalling can be regulated in a
number of different ways:
• Affinity of ligand for receptor – high affinity/transient interaction
• Duration of the interaction
• Internalisation of the receptor – dragged into the interior of the
cell by endocytosis and destroyed by digestion in lysosomes
(which contain proteolytic enzymes)
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Receptor Tyrosine Kinases:
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RTK Families:
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There are 58 known RTKs in humans, 29 of which are known protooncogenes
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EGFR are the first RTKs to be characterised – EGFR sequencing by
Waterfield’s lab revealed homology to v-erbB (one of two oncogenes
carried by the avian erythroblastosis virus)
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V-erbB is a truncated form of the avian EGFR gene (ErbB1)
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EGFR/ErbB-1 is the prototype receptor tyrosine kinase
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EGF family receptors are expressed in almost all types of tissue
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à ErbB-3/HER3 has no kinase activity
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EGF is a monomeric growth factor ligand – therefore, it binds to 2
separate sites on the receptor, i
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the receptor requires two EGF
molecules
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Binding of EGF changes the conformation of the receptor and
allows dimerization to occur
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Ligand-stabilized conformation – the binding of the ligand to its
binding site stabilizes the receptor
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Ligand-induced activated dimers – refers to the dimerization event
that produces two phosphorylation events to occur
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Either homodimers or heterodimers are formed
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ErbB-2 & ErbB-4
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EGFR and Disease:
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This creates directionality of the cell growth
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Can we target this interaction?
“ib” – inhibitor
“ab” – monoclonal antibody
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PDGF Receptor:
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PDGFR mutations in cancer:
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FGF Receptor Structure:
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• Heparin/ Heparin sulphate is required for FGF binding:
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Here, heparin is
acting as a scaffold, suggesting that the affinity of FGF is not very high
(due to the high ligand to receptor ratio), and thus, heparin stabilizes FGF
long enough to allow dimerization
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A current proposed model as to the interaction is:
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HGF Receptor:
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TGF-b Receptors:
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• Type II – 70-100kDA glycoprotein with an intracellular serine/threonine
kinase domain
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• TGF-b and Cancer:
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IGF Receptor:
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IGF and Cancer:
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Summary of RTKs:
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Non-Receptor Tyrosine Kinases – Src:
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C-src is
“locked” in its inactive conformation by the presence of Tyr527 on the cterminal
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Src family tyrosine kinases share 3 homologous domains:
• SH1 – TK domain
• SH2 – binding site for phosphotyrosine (phosphorylated tyrosines)
• SH3 – binding site for proline-rich motifs
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Beyond the Receptor:
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increased transcription occurs within minutes
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