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JCS ePress online publication date 18 Mar 2008
doi: 10.1242/jcs.018713


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Research Article

Transforming signals resulting from sustained activation of the PDGF{beta} receptor in mortal human fibroblasts


Lisa M. Petti*, Elizabeth C. Ricciardi, Heather J. Page, and Kristen A. Porter
* Author for correspondence (e-mail: pettil{at}mail.amc.edu)

The platelet-derived growth factor {beta} receptor (PDGF{beta}R) plays an important role in proliferation and motility of fibroblasts. We have been investigating the effects of sustained PDGF{beta}R activation in mortal human diploid fibroblasts (HDFs), which are typically difficult to transform. We have previously shown that the bovine papillomavirus E5 protein, through its ability to crosslink and constitutively activate the PDGF{beta}R, induces morphological transformation, enhanced growth and loss of contact inhibition (focus formation) in HDFs. Here, we characterized two E5 mutants as being severely defective for focus formation but still competent for enhanced growth, suggesting that proliferation is insufficient for loss of contact inhibition. These E5 mutants were then used in a comparative study to distinguish the PDGF{beta}R signaling intermediates required for the enhanced growth phenotype from those required for focus formation. Our data suggested that a PI 3-kinase (PI3K)-AKT-cyclin D3 pathway, a Grb2-Gab1-SHP2 complex and JNK played a role in the enhanced growth phenotype. However, a SHP2-p66Shc-p190BRhoGAP complex and ROCK were implicated exclusively in focus formation. We speculate that a SHP2-p66Shc-p190BRhoGAP signaling complex recruited to the activated PDGF{beta}R promotes a distinct Rho-dependent process required for focus formation but not growth of HDFs.







© The Company of Biologists Ltd 2008