title: Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment.
abstract: 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.
authors.affiliation: Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico jvazquez@cinvestav.mx greyesc@cinvestav.mx.
authors.forename: José
authors.initials: J
authors.lastname: Vázquez-Prado
authors.affiliation: Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico.
authors.forename: Ismael
authors.initials: I
authors.lastname: Bracho-Valdés
authors.affiliation: Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico.
authors.forename: Rodolfo Daniel
authors.initials: RD
authors.lastname: Cervantes-Villagrana
authors.affiliation: Departments of Pharmacology (J.V.-P., R.D.C.-V.) and Cell Biology (G.R.-C.). CINVESTAV-IPN, Mexico City, and Department of Pharmacology (I.B.-V.), School of Medicine, UABC, Mexicali, B.C., Mexico jvazquez@cinvestav.mx greyesc@cinvestav.mx.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Reyes-Cruz
mesh_terms: D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D043562:Receptors, G-Protein-Coupled