American Association for Cancer Research, Clinical Cancer Research, 17(19), p. 4564-4569, 2013
DOI: 10.1158/1078-0432.ccr-12-1662
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Abstract P-Rex proteins are Rho/Rac guanine nucleotide exchange factors that participate in the regulation of several cancer-related cellular functions such as proliferation, motility, and invasion. Expectedly, a significant portion of these actions of P-Rex proteins must be related to their Rac regulatory properties. In addition, P-Rex proteins control signaling by the phosphoinositide 3-kinase (PI3K) route by interacting with PTEN and mTOR. The interaction with PTEN inhibits its phosphatase activity, leading to AKT activation. The interaction with mTOR may be important in nutrient-stimulated Rac activation and migration. In humans, several studies have implicated P-Rex proteins in the pathophysiology of various neoplasias. Thus, overexpression of P-Rex proteins has been linked to poor patient outcome in breast cancer and may facilitate metastatic dissemination of prostate cancer cells. In addition, whole-genome sequencing described P-Rex2 as a significantly mutated gene in melanoma. Furthermore, expression in melanocytes of mutated forms of P-Rex2 found in patients with melanoma showed the protumorigenic role of these P-Rex mutations in melanoma genesis. These findings open interesting opportunities for P-Rex targeting in cancer. Moreover, the implication of P-Rex partner proteins such as Rac, mTOR, or PTEN in cancer has opened the possibility of acting on P-Rex to restrict protumorigenic signaling through these pathways. Clin Cancer Res; 19(17); 4564–9. ©2013 AACR.