BCH3042 Lecture Notes - Lecture 7: Growth Factor, Intrinsically Disordered Proteins, Orphan Receptor
25 May 2018
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Lecture 7 – Epidermal Growth Factor Receptor (EGFRs)
Tyrosine Phosphorylation
• Tyrosine residue in proteins – very specific
• Single phosphate group added by family of kinases (protein tyrosine kinase:
PTK)
• Two types:
o Receptor PTKs (59)
▪ Membrane bound
▪ Intracellular domain
o Non-receptor PTKs (32)
Epidermal Growth Factor Receptors (EGFRs)
What are they?
• Cells responding to signals from external environment
• EGFR family is a family of Receptor PTK
• Comprised of 4 members:
o EGFR/ErbB1
o HER2/ErbB2
o HER3/ErbB3
o HER4/ErbB4
▪ Her1,2 and 4 have protein kinase domain
▪ Her3, doesn’t signal (no tyrosine domain)
▪ Her 2 has no ligand to bind (orphan receptor)
▪ Multiple ligands per receptor
• HER = Human Epidermal Growth Factor Receptor
• Erb = Erthroblastic leukemia viral oncogene – virally encoded homologous
protein
• ErbBs – widely expressed in epithelial, mesenchymal and neuronal cells
o Regulate fundamental processes in adult cells including cellular
growth and proliferation, migration, differentiation and survival
▪ Cancer exploits this pathway – attract target to control cancer
o Excessive ErbB signalling is associated with development and
malignancy of solid tumours
How are they Activated?
• Epidermal growth factor (EGF) – small secreted protein (6 kDa)
• EGF binds to EGFR on cells to induce intracellular signal transduction and
effects on cell proliferation and survival
• Inactive form: no ligand
• Tethered monomer → ligand (e.g. EGF) binds to EGFR → causes
conformational change → dimerization → transphorylation of activation loop
→ autophosphorylation on C-terminal tail domain of EGFR→ form activated
hetero-dimers e.g. tyrosine phosphorylated proteins
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Document Summary
Lecture 7 epidermal growth factor receptor (egfrs) Tyrosine phosphorylation: tyrosine residue in proteins very specific, single phosphate group added by family of kinases (protein tyrosine kinase: Ptk: two types, receptor ptks (59, membrane bound. How are they activated: epidermal growth factor (egf) small secreted protein (6 kda, egf binds to egfr on cells to induce intracellular signal transduction and effects on cell proliferation and survival. Inactive form: no ligand: tethered monomer ligand (e. g. egf) binds to egfr causes conformational change dimerization transphorylation of activation loop. Autophosphorylation on c-terminal tail domain of egfr form activated hetero-dimers e. g. tyrosine phosphorylated proteins: egfr enhances transactivation by gpcrs. Integrates multiple pathways large factor on growth and survival. Turning off egfr signalling: dephosphorylation of the intracellular tail of the receptor, kinase domain is no longer active, binding sites are gone, carried out by ptp several dephosphorylate erbb1, ptp1b (ptpn1, tcptp (ptpn2, ptp-pest (ptpn12)
