G Protein-Coupled Receptors in Cancer

Abstract

Despite the fact that G protein-coupled receptors (GPCRs) are the largest signal-conveying receptor family and mediate many physiological processes, their role in tumor biology is underappreciated. Numerous lines of evidence now associate GPCRs and their downstream signaling targets in cancer growth and development. Indeed, GPCRs control many features of tumorigenesis, including immune cell-mediated functions, proliferation, invasion and survival at the secondary site. Technological advances have further substantiated GPCR modifications in human tumors. Among these are point mutations, gene overexpression, GPCR silencing by promoter methylation and the number of gene copies. At this point, it is imperative to elucidate specific signaling pathways of "cancer driver" GPCRs. Emerging data on GPCR biology point to functional selectivity and "biased agonism"; hence, there is a diminishing enthusiasm for the concept of "one drug per GPCR target" and increasing interest in the identification of several drug options. Therefore, determining the appropriate context-dependent conformation of a functional GPCR as well as the contribution of GPCR alterations to cancer development remain significant challenges for the discovery of dominant cancer genes and the development of targeted therapeutics.

Keywords: CXCR4; G protein-coupled receptors (GPCRs); Hippo/YAP; LPA(1-6); PH-domain; Wnt/β-catenin; cancer; oncogenes; protease; protease-activated receptor; protease-activated receptors (PARs).

Scheme 1

Illustration of Wnt/β-catenin canonical and noncanonical pathways. In the presence of a Wnt ligand (e.g., Wnt 3A), Frizzled receptor (Fz) co-associates with LRP5/6, leading to stabilization of β-catenin. In contrast, in the absence of a Wnt ligand, β-catenin is rapidly degraded via the proteasomal compartment. Stabilized β-catenin enters the nuclei and functions as a co-transcription factor, inducing a spectrum of gene signature downstream. Noncanonical Wnt signaling (e.g., Wnt 5a) is mediated via Fz affecting, among others, activation of JNK and the cytoskeleton. Rred cross: Inhibition of signal cascade.

Scheme 2

The Hippo/YAP pathway is physiologically initiated via GPCRs. The Hippo pathway takes place following the phosphorylation of Ltats1/2 by Mst1/2 which leads to the phosphorylation of YAP and its anchoring localization in the cytoplasmic compartment. YAP is activated by inhibition of the Hippo pathway via the de-phosphorylation of YAP, resulting in YAP nuclear localization and its function as a co-transcription factor.

Scheme 3

PH domains power tumor growth. The activation of PAR_1&2 results in binding of PH signal proteins. These association motifs are essential for tumor development. The “inside-out” mode of integrin activation via either PH-Etk/Bmx-FERM/FAK or PH-Rgnef-FAK can induce interactions with PARs through all stages of cancer development.