Adhesion GPCRs in Tumorigenesis

Abstract

Alterations in the homeostasis of several adhesion GPCRs (aGPCRs) have been observed in cancer. The main cellular functions regulated by aGPCRs are cell adhesion, migration, polarity, and guidance, which are all highly relevant to tumor cell biology. Expression of aGPCRs can be induced, increased, decreased, or silenced in the tumor or in stromal cells of the tumor microenvironment, including fibroblasts and endothelial and/or immune cells. For example, ADGRE5 (CD97) and ADGRG1 (GPR56) show increased expression in many cancers, and initial functional studies suggest that both are relevant for tumor cell migration and invasion. aGPCRs can also impact the regulation of angiogenesis by releasing soluble fragments following the cleavage of their extracellular domain (ECD) at the conserved GPCR-proteolytic site (GPS) or other more distal cleavage sites as typical for the ADGRB (BAI) family. Interrogation of in silico cancer databases suggests alterations in other aGPCR members and provides the impetus for further exploration of their potential role in cancer. Integration of knowledge on the expression, regulation, and function of aGPCRs in tumorigenesis is currently spurring the first preclinical studies to examine the potential of aGPCR or the related pathways as therapeutic targets.

Keywords: Metastasis; Tumor angiogenesis; Tumor cell migration; Tumor invasion; Tumor therapy.

Fig. 1

Structure and functions of BAIs (ADGRBs). (a) Schematic of the three BAI proteins, representing the major known structural and functional features as well as known proteolysis events that generate either Vstat120 [69] or Vstat40 [71], and cancer-associated somatic mutations [21, 122]. Abbreviations: TSR thrombospondin type 1 repeat, GAIN GPCR autoproteolysis-inducing domain [123], GPS GPCR-proteolytic site, 7TM seven-transmembrane region, RGD Arg-Gly-Asp integrin-binding motif, PRR proline-rich region. (b) Multiple functions of BAI1: BAI1 inhibits tumor cell growth in part by inhibiting angiogenesis. Moreover, its TSRs interact with exposed phosphatidylserine at the outer leaflet on apoptotic cells and elicit the engulfment in macrophages (Mϕ). BAI1 also promotes myogenesis. Deficiency of BAI1 promotes PSD-95 degradation at the synapses and induces enhanced long-term potentiation. Figure adapted from [124]