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 PIP(3)-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.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Sosa
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lopez-Haber
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
authors.forename: Hongbin
authors.initials: H
authors.lastname: Wang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.forename: John M
authors.initials: JM
authors.lastname: Busillo
authors.forename: Jiansong
authors.initials: J
authors.lastname: Luo
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Ramon E
authors.initials: RE
authors.lastname: Parsons
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Kazanietz
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D018739:Oncogene Proteins v-erbB; C453280:PREX1 protein, human; D020830:rac1 GTP-Binding Protein