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

doi:10.1016/j.molcel.2010.11.029

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

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

167 Scopus citations

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 language	English
Pages (from-to)	877-892
Number of pages	16
Journal	Molecular Cell
Volume	40
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2010.11.029
State	Published - Dec 22 2010

Bibliographical note

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.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sosa, M. S., Lopez-Haber, C., Yang, C., Wang, H. B., Lemmon, M. A., Busillo, J. M., Luo, J., Benovic, J. L., Klein-Szanto, A., Yagi, H., Gutkind, J. S., Parsons, R. E., & Kazanietz, M. G. (2010). Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer. Molecular Cell, 40(6), 877-892. https://doi.org/10.1016/j.molcel.2010.11.029

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

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.",

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

note = "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. ",

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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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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