TY - JOUR
T1 - Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer
AU - Sosa, Maria Soledad
AU - Lopez-Haber, Cynthia
AU - Yang, Chengfeng
AU - Wang, Hong Bin
AU - Lemmon, Mark A.
AU - Busillo, John M.
AU - Luo, Jiansong
AU - Benovic, Jeffrey L.
AU - Klein-Szanto, Andres
AU - Yagi, Hiroshi
AU - Gutkind, J. Silvio
AU - Parsons, Ramon E.
AU - Kazanietz, Marcelo G.
N1 - Funding Information:
This work is supported by grants R01CA74197, R01CA129133, and R01CA139120 (NIH) and KG090522 (Susan Komen Foundation for the Cure) to M.G.K. and by grant R01CA129626 to J.L.B. H.Y. and J.S.G. are supported by the Intramural Program, NIDCR, NIH. R.E.P. is supported by grant R01CA155117. We thank Andy Cucchiara (UPenn) for help with statistical analyses and Celine Lefebvre (Columbia University) for support with microarray data analysis.
PY - 2010/12/22
Y1 - 2010/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78650235523&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2010.11.029
DO - 10.1016/j.molcel.2010.11.029
M3 - Article
C2 - 21172654
AN - SCOPUS:78650235523
SN - 1097-2765
VL - 40
SP - 877
EP - 892
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -