Fig. 3.

GPR56 signaling in pathological processes. (A) In a colorectal cancer (CRC) cell, progastrin (PG) binds to GPR56 and promotes the epithelial-to-mesenchymal transition and metastasis by the PI3K/Akt pathway. Moreover, GPR56 also promotes drug resistance by promoting MDR1 expression via the RhoA pathway [[83], [84], [85]]. (B) GPR56 inhibits the metastasis and tumor survival in a melanoma cell by internalization and degradation of TG2-bound GPR56 thereby controlling the concentration of TG2 in ECM which is a major promoter of tumor survival [46,104]. An alternative mechanism observed in melanoma cells is the interaction of GPR56 with tetraspanins such as CD81, which recruit Gα_q/11(Gβγ) heterotrimer and finally inhibits VEGF secretion, and hence the angiogenesis, via the PKCα pathway [72,104]. (C) In the HT1080 cell line, heparin has been demonstrated to bind to the NTF of GPR56 [32,104]. One of the major heparin-binding sites of GPR56 overlaps with the collagen III-binding site, hence making heparin capable of modulating the binding and signaling by collagen III [32]. It is observed that the binding of heparin reduces NTF shedding and promotes cell motility and adhesion [32]. (D) In U87-MG cells, GPR56 inhibits cell migration via the Gα_q and Rho pathway [81]. Moreover, GPR56 also inhibits mesenchymal transition and radioresistance by inhibiting the NF-κB signaling pathway upstream of NEMO [82]. TNF activates the TNF receptor which promotes mesenchymal transition and radioresistance by activating NF-κB signaling pathway and downregulating GPR56 indirectly [82]. The solid lines represent direct interaction, whereas the dotted lines indicate indirect pathways with potential additional intermediate(s).