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The role of Shc in growth factor receptor signaling

Jeremy Copp

Appointment Period: 2001-2003, Grant Years: [17,18]

Jeremy CoppShc is a member of a highly conserved family of adaptor proteins that act downstream of receptors for a variety of extracellular messengers, including several oncogenically activated growth factor receptors. Shc lacks a recognizable catalytic domain but is well equipped for protein-protein interactions. It contains both an amino-terminal phosphotyrosine-binding (PTB)domain and a carboxy-terminal Src-homology 2 (SH2) domain. Shc is itself phosphorylated on at least three tyrosine residues that function as binding sites for other proteins. In the current model for Shc function downstream of growth factor receptor protein-tyrosine kinases, Shc uses its PTB domain toassociate with activated receptors. Upon association with these receptors, Shcbecomes tyrosine phosphorylated, creating a docking site for another cytoplasmicadaptor molecule, Grb-2. In this model, the sole function of Shc is to linkGrb-2 to activated growth factor receptors. We created growth factor receptor mutants where a traditional Shc binding site has been destroyed and replaced with a Grb-2 binding site. If the sole function of Shc is to link Grb-2 to activated receptors, then a receptor that bypasses the need for Shc and binds directly to Grb-2 should retain its signaling capabilities. We found that the receptor mutant that no longer binds to Shc is deficient in activating downstream signaling events. Replacing the Shc binding site with a Grb-2binding site does not rescue receptor signaling. Our results suggest that the function of Shc is more complicated than solely linking Grb-2 to activated growth factor receptors.

Copp J,Marino M, Banerjee M, Ghosh P, van der Geer P. Multiple regions of internalin B contribute to its ability to turn on the Ras-mitogen-activated protein kinase pathway. J Biol Chem. (2003)278:7783-9. PMID: 12488439.

MarinoM, Banerjee M, Copp J, Dramsi S,Chapman T, van der Geer P, Cossart P, Ghosh P. Characterization of the calcium-binding sites of Listeriamonocytogenes InlB. Biochem BiophysRes Commun. (2004) 316:379-86. PMID: 15020228.

Banerjee M, Copp J, Vuga D, Marino M, ChapmanT, van der Geer P, Ghosh P. GW domains of the Listeria monocytogenes invasion protein InlB are required forpotentiation of Met activation. Mol Microbiol. (2004) 52:257-71. PMID: 15049825.

Wilhelmsen K, Copp J, Glenn G, Hoffman RC,Tucker P, van der Geer P. Purification and identification of protein-tyrosinekinase-binding proteins using synthetic phosphopeptides as affinity reagents. Mol Cell Proteomics. (2004) 3:887-95.PMID: 15215307.

Copp J, Wiley S, Ward MW, van der Geer P. Hypertonic shock inhibits growth factorreceptor signaling, induces caspase-3 activation, and causes reversible fragmentation of the mitochondrial network. AmJ Physiol Cell Physiol. (2005) 288:C403-15. PMID: 15456696.

Copp J, Manning G, Hunter T. TORC-specific phosphorylation of mammalian target ofrapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex2. Cancer Res. (2009) 691821-7. PMID:19244117; PMCID: PMC2652681.