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.

Chemokine-biased robust self-organizing polarization of migrating cells in vivo

“…Many of the studies on the polarization of migrating cells highlight the role of biochemical signaling pathways (e.g. small GTPases, GEFs, PI3P signaling) 41,42,44 that define the front or the rear and the inhibitory interaction between them 8,45 . Our work underscores the importance of biophysical parameters in polarity establishment and maintenance in migrating cells.…”

Identification of novel regulatory partners of the glutamate transporter GLT‐1

“…Whether this interaction is responsible for the altered kinetics observed requires further study, although this may involve several mechanisms, including an allosteric effect due to protein–protein interactions, posttranslational modifications of the transporter (e.g., phosphorylation or ubiquitination; Ibanez, Diez‐Guerra, Gimenez, & Zafra, ), or indirect effects on the lipidic or ionic transporter milieu. Indeed, the number of Gβγ‐regulated signaling molecules is still expanding, and this includes the aforementioned activation of PI3K and downstream signaling through the AKT/mTOR or ERK pathways (revised in Vazquez‐Prado, Bracho‐Valdes, Cervantes‐Villagrana, & Reyes‐Cruz, ), as well as modifications to ion channel activity (review in Betke, Wells, & Hamm, ). Like Rac1, we found Gβγ activity to have a cell specific effect, whereby GLAST was not affected by mSIRK in transfected cells (Garcia‐Olivares et al, ) but it was inhibited significantly in mixed cultures.…”

Statins Perturb GβγSignaling and Cell Behavior in a GγSubtype Dependent Manner

“…Cell migration and invasion play a critical role in cancer cell progression and subsequent cancer metastasis (Kirui et al, 2010). The role of Gbg signaling in cell migration and invasion is thoroughly investigated and well documented (Kirui et al, 2010;Tang et al, 2011;Kim et al, 2012;Vázquez-Prado et al, 2016). In addition to PI3K, Gbg signaling contributes to full activation of PIP3-dependent Rac exchanger 1 (P-Rex1) and thus to Rac1-mediated cell mobility (Dbouk et al, 2012;Kim et al, 2012).…”