Margolis_post - Receptor tyrosine kinase signaling -...

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Receptor tyrosine kinase signaling - Background A. EGF Receptor •Member of RTK family •Binds epidermal growth factor (EGFR) •Promotes cell proliferation •e.g., mammary epithelium and epidermis •necessary for formation of epithelial linings of the esophagus, mouth and cornea. •erbB oncogene encodes a mutant form of the receptor that is constitutively active. •EGFR belongs to a family of very similar proteins that also includes ErbB2, ErbB3 and ErbB4
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Receptor tyrosine kinase signaling - Background Multiple tyrosine phosphorylation sites typically create multiple binding sites for different effectors of RTK signaling B. Activation of RTKs •Ligand binding causes receptor to dimerize. •Receptor phosphorylates itself on tyrosine residues - auto cross-phosphorylation. •Phosphotyrosine residues on receptor are now targets for interaction with other proteins involved in signal transduction. •Act as docking sites for binding of effectors or adapters •Some of the proteins interacting with the receptor become activated by phosphorylation on tyrosine residues
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Phospholipase C (PLC) - Reminder (MBOC 15-30) • PLC cleaves phosphatidylinositol-bisphosphate into two second messengers 1. inositol trisphosphate (IP3) •IP3 triggers Ca++ release from the ER. •In turn, Ca++ activates a serine/threonine kinase via its interaction with calmodulin 2. diacylglycerol (DAG). •Diacylgycerol activates protein kinase C which in turn activates a kinase cascade • several forms of PLC •PLC -II is same as PLC γ •(this is the form in the paper) •PLC β is activated by a trimeric G protein
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Margolis et al. EGF induces tyrosine phosphorylation of phopholipase C-II: A potential mechanism for EGF receptor signaling A. Major Questions What are the effectors of EGF cell signaling? What are the downstream targets of the EGF receptor (EGFR)? Might expect target to bind specifically to the activated (phosphorylated) EGFR Might expect target itself to become phosphorylated upon activation of EGFR possible approach could be to identify proteins that are newly phosphorylated with radioactive 32 P. Or predictions about possible effectors can be made based on the knowledge of
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This note was uploaded on 10/19/2009 for the course B M B 460 taught by Professor Hanna-rose,w during the Spring '08 term at Pennsylvania State University, University Park.

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Margolis_post - Receptor tyrosine kinase signaling -...

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