Reciprocal Regulation of Neu Tyrosine Kinase Activity and Caveolin-1 Protein Expression in Vitro and in Vivo

• DOI: 10.1074/jbc.273.32.20448
• Publication Date: 2002-07-26T15:02:22Z
• Authors: Jeffrey A. Engelman; Richard J. Lee; Anthony Karnezis; David J. Bearss; Marc Webster; Peter Siegel; William J. Muller; Jolene J. Windle; Richard G. Pestell; Michael P. Lisanti
• Keywords: Caveolin 1; Reciprocal

<i>Neu</i> (c-<i>erbB2</i>) is a proto-oncogene product that encodes an epidermal growth factor-like receptor tyrosine kinase. Amplification of wild-type c-<i>Neu</i>and mutational activation (<i>Neu T</i>) have been implicated in oncogenic transformation cultured fibroblasts and mammary tumorigenesis <i>in vivo</i>. Here, we examine the relationship between Neu kinase activity caveolin-1 protein expression vitro</i> vivo.</i> Recent studies suggested caveolins may function as negative regulators signal transduction. Our current results show c-Neu down-regulates expression, but not caveolin-2, NIH 3T3 Rat 1 cells. Conversely, recombinant overexpression blocks Neu-mediated transduction These suggest reciprocal expression. We next analyzed variety deletion mutants to map this caveolin-1-dependent inhibitory given region molecule. Results from analysis functional vivo</i> contained within residues 32–95. In accordance with these<i>in studies, 20-amino acid peptide derived (the scaffolding domain) was sufficient inhibit autophosphorylation assay. To further confirm or refute relevance our findings vivo</i>, examined levels tumors transgenic mice. indicate dramatic reduction occurs c-Neu-expressing mice other expressing downstream effectors transduction, such Src Ras. Taken together, data novel form regulation exists caveolin-1.