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Sosa MS , Lopez-Haber C , Yang CF , Wang HB , Lemmon MA , Busillo JM , Luo JS , Benovic JL , Klein-Szanto A , Yagi H , Gutkind JS , Parsons RE , Kazanietz MG
Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer
Molecular Cell. 2010 Dec;40(6) :877-892
PMCID: PMC3038344   
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Abstract
While the small GTPase Rac1 and its effectors are well-established mediators of mitogenic and motile signaling by tyrosine kinase receptors and have been implicated in breast tumorigenesis, little is known regarding the exchange factors (Rac-GEFs) that mediate ErbB receptor responses. Here, we identify the PIP3-G beta gamma-dependent Rac-GEF P-Rex1 as an essential mediator of Rac1 activation, motility, cell growth, and tumorigenesis driven by ErbB receptors in breast cancer cells. Notably, activation of P-Rex1 in breast cancer cells requires the convergence of inputs from ErbB receptors and a G beta gamma- and PI3K gamma-dependent pathway. Moreover, we identified the GPCR CXCR4 as a crucial mediator of P-Rex1/Rac1 activation in response to ErbB ligands. P-Rex1 is highly overexpressed in human breast cancers and their derived cell lines, particularly those with high ErbB2 and ER expression. In addition to the prognostic and therapeutic implications, our findings reveal an ErbB effector pathway that is crucial for breast cancer progression.
Notes
Sosa, Maria Soledad Lopez-Haber, Cynthia Yang, Chengfeng Wang, HongBin Lemmon, Mark A. Busillo, John M. Luo, Jiansong Benovic, Jeffrey L. Klein-Szanto, Andres Yagi, Hiroshi Gutkind, J. Silvio Parsons, Ramon E. Kazanietz, Marcelo G. Cell press Cambridge 701nf