TY - JOUR T1 - G<em>βγ</em> Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment JF - Molecular Pharmacology JO - Mol Pharmacol SP - 573 LP - 586 DO - 10.1124/mol.116.105338 VL - 90 IS - 5 AU - José Vázquez-Prado AU - Ismael Bracho-Valdés AU - Rodolfo Daniel Cervantes-Villagrana AU - Guadalupe Reyes-Cruz Y1 - 2016/11/01 UR - http://molpharm.aspetjournals.org/content/90/5/573.abstract N2 - Cancer cells and stroma cells in tumors secrete chemotactic agonists that exacerbate invasive behavior, promote tumor-induced angiogenesis, and recruit protumoral bone marrow–derived cells. In response to shallow gradients of chemotactic stimuli recognized by G protein–coupled receptors (GPCRs), Gβγ-dependent signaling cascades contribute to specifying the spatiotemporal assembly of cytoskeletal structures that can dynamically alter cell morphology. This sophisticated process is intrinsically linked to the activation of Rho GTPases and their cytoskeletal-remodeling effectors. Thus, Rho guanine nucleotide exchange factors, the activators of these molecular switches, and their upstream signaling partners are considered participants of tumor progression. Specifically, phosphoinositide-3 kinases (class I PI3Ks, β and γ) and P-Rex1, a Rac-specific guanine nucleotide exchange factor, are fundamental Gβγ effectors in the pathways controlling directionally persistent motility. In addition, GPCR-dependent chemotactic responses often involve endosomal trafficking of signaling proteins; coincidently, endosomes serve as signaling platforms for Gβγ. In preclinical murine models of cancer, inhibition of Gβγ attenuates tumor growth, whereas in cancer patients, aberrant overexpression of chemotactic Gβγ effectors and recently identified mutations in Gβ correlate with poor clinical outcome. Here we discuss emerging paradigms of Gβγ signaling in cancer, which are essential for chemotactic cell migration and represent novel opportunities to develop pathway-specific pharmacologic treatments. ER -