Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger (P-Rex) proteins are RacGEFs that are synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and Gβγ subunits of G-protein-coupled receptors. P-Rex1 and P-Rex2 share similar amino acid sequence homology, domain structure, and catalytic function. Recent evidence suggests that both P-Rex proteins may play oncogenic roles in human cancers. P-Rex1 and P-Rex2 are altered predominantly via overexpression and mutation, respectively, in various cancer types, including breast cancer, prostate cancer, and melanoma. This review compares the similarities and differences between P-Rex1 and P-Rex2 functions in human cancers in terms of cellular effects and signalling mechanisms. Emerging clinical data predict that changes in expression or mutation of P-Rex1 and P-Rex2 may lead to changes in tumour outcome, particularly in breast cancer and melanoma.

PtdIns(3,4,5)P 3 -dependent Rac exchanger 1 (PREX1) is a Racguanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane surface receptors. However, the PREX1 domains that facilitate its oncogenic activity and downstream signaling are not completely understood. We identify that ERK1/2 MAPK acts downstream of PREX1 and contributes to PREX1-mediated anchorage-independent cell growth. PREX1 overexpression increased but its shRNA knockdown decreased ERK1/2 phosphorylation in response to EGF/IGF-1 stimulation, resulting in induction of the cell cycle regulators cyclin D1 and p21 WAF1/CIP1. PREX1-mediated ERK1/2 phosphorylation, anchorage-independent cell growth, and cell migration were suppressed by inhibition of MEK1/2/ERK1/2 signaling. PREX1 overexpression reduced staurosporine-induced apoptosis whereas its shRNA knockdown promoted apoptosis in response to staurosporine or the anti-estrogen drug tamoxifen. Expression of wild-type but not GEF-inactive PREX1 increased anchorage-independent cell growth. In addition, mouse xenograft studies revealed that expression of wild-type but not GEF-dead PREX1 resulted in the formation of larger tumors that displayed increased phosphorylation of ERK1/2 but not AKT. The impaired anchorage-independent cell growth, apoptosis, and ERK1/2 signaling observed in stable PREX1 knockdown cells was restored by expression of wild-type but not GEF-dead-PREX1. Therefore, PREX1-Rac-GEF activity is critical for PREX1-dependent anchorage-independent cell growth and xenograft tumor growth and may represent a possible therapeutic target for breast cancers that exhibit PREX1 overexpression.The Rac proteins (Rac1, Rac2, and Rac3) are a subgroup of the Rho-GTPase family that regulate cell motility and, when deregulated, drive cancer invasion and metastasis (1-3). Rac proteins undergo rapid and spatiotemporally coordinated cycles of activation and inactivation linked to upstream receptor signaling by guanine nucleotide exchange factors (GEFs) 2 (4). The most common mechanism for Rac hyperactivation in human cancer is via dysregulation of Rac-GEF activity. PtdIns (3,4,5)P 3 -dependent Rac exchanger 1 (PREX1) is a member of the Dbl family of Rho-GEFs that promotes chemoattractantstimulated neutrophil chemotaxis and reactive O 2 species formation (5-7). PREX1 is a multidomain protein that contains an N-terminal catalytic Dbl-homologous (DH) domain, which activates Rac, adjacent to a pleckstrin homology (PH) domain, which binds to and is activated by PI3K-generated PtdIns(3,4,5)P 3 , followed by two dishevelled, EGL-10 and pleckstrin (DEP) domains, two PDZ domains, and a catalytically inactive C-terminal inositol polyphosphate 4-phosphatase (IP4P) domain, which shares 30% amino acid identity with the catalytically active IP4P domain of the inositol polyphosphate 4-phosphatases INPP4A and INPP4B (5,8,9). The IP4P domain of PREX1 contains a common catalytic CX 5 R motif shared by dual specificity p...

The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of PREX1 mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher PREX1 mRNA in ER+ve/luminal tumors was associated with poor outcome in luminal B cancers. Prex1 deletion in MMTV-neu or MMTV-PyMT mice reduced Rac1 activation in vivo and improved survival. High level MMTV-driven transgenic PREX1 expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV-PREX1 expression in MMTV-neu mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.

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