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PMID:21349850

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Citation

McNulty, DE, Li, Z, White, CD, Sacks, DB and Annan, RS (2011) MAPK scaffold IQGAP1 binds the EGF receptor and modulates its activation. J. Biol. Chem. 286:15010-21

Abstract

Cellular responses produced by EGF are mediated through the receptor (EGFR) and by various enzymes and scaffolds. Recent studies document IQGAP1 as a scaffold for the MAPK cascade, binding directly to B-Raf, MEK, and ERK and regulating their activation in response to EGF. We previously showed that EGF is unable to activate B-Raf in cells lacking IQGAP1. However, the mechanism by which IQGAP1 links B-Raf to EGFR was unknown. Here we report that endogenous EGFR and IQGAP1 co-localize and co-immunoprecipitate in cells. EGF has no effect on the association, but Ca(2+) attenuates binding. In vitro analysis demonstrated a direct association mediated through the IQ and kinase domains of IQGAP1 and EGFR, respectively. Calmodulin disrupts this interaction. Using a mass spectrometry-based assay, we show that EGF induces phosphorylation of IQGAP1 Ser(1443), a residue known to be phosphorylated by PKC. This phosphorylation is eliminated by pharmacological inhibition of either EGFR or PKC and transfection with small interfering RNA directed against the PKCĪ± isoform. In IQGAP1-null cells, EGF-stimulated tyrosine phosphorylation of EGFR is severely attenuated. Normal levels of autophosphorylation are restored by reconstituting wild type IQGAP1 and enhanced by an IQGAP1 S1443D mutant. Collectively, these data demonstrate a functional interaction between IQGAP1 and EGFR and suggest that IQGAP1 modulates EGFR activation.

Links

PubMed PMC3083173 Online version:10.1074/jbc.M111.227694

Keywords

Animals; Humans; MAP Kinase Signaling System; Mice; Phosphorylation; Protein Binding; Proto-Oncogene Proteins B-raf; Receptor, Epidermal Growth Factor/metabolism; ras GTPase-Activating Proteins/metabolism

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