Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer

Maria Soledad Sosa, Cynthia Lopez-Haber, Chengfeng Yang, Hong Bin Wang, Mark A. Lemmon, John M. Busillo, Jiansong Luo, Jeffrey L. Benovic, Andres Klein-Szanto, Hiroshi Yagi, J. Silvio Gutkind, Ramon E. Parsons, Marcelo G. Kazanietz

Research output: Contribution to journalArticlepeer-review

134 Citations (Scopus)

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-Gβγ-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 Gβγ- and PI3Kγ-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.

Original languageEnglish
Pages (from-to)877-892
Number of pages16
JournalMolecular Cell
Volume40
Issue number6
DOIs
Publication statusPublished - Dec 22 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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