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 specify 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, and 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 Gβγ 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 pharmacological treatments.
- Chemotactic peptides
- Gi family
- G12,13;other G's
- G[beta][gamma] signaling
- GEFs (non-receptor)
- Rac
- Rho
- Cdc42, rho, rac, other small G proteins
- Oncogenes
- The American Society for Pharmacology and Experimental Therapeutics