A noncanonical-GPRC5A signaling regulates keratinocyte adhesion and migration by nuclear translocation

G-Protein Coupled Receptor, Class C, Group 5, Member A (GPRC5A) has been extensively studied in lung and various epithelial cancers. Nevertheless, its role in the skin remains to be elucidated. In this study, we sought to investigate the function of this receptor in skin biology. Our research demonstrated that its expression responds to mechanical substrate changes in human primary keratinocytes. Furthermore, we observed the reinduction of GPRC5A during wound healing at the leading edges in an ex vivo burn model, coinciding with the translocation of its C-terminal region into the nucleus. We identified the cleavage site of GPRC5A by N-TAILS analysis, and cathepsin G was characterized as the protease responsible for proteolysis in cultured cells. In order to gain a deeper understanding of the role of GPRC5A in keratinocytes, we performed a GPRC5A knockdown in N/TERT-1 cells using short-hairpin RNA. Our findings indicate a strong association between GPRC5A and adhesion regulation pathways. Additionally, our results demonstrate that GPRC5A^KD enhances cell adhesion while reducing cell migration and differentiation. It is noteworthy that these effects were reversed by the addition of a recombinant polypeptide that mimics the C-terminal region of GPRC5A. In conclusion, our study reveals that GPRC5A plays an unexpected role in regulating keratinocyte behavior, with implications for its C-terminal region translocation into the nucleus. These results offer promising avenues for future research in the field of wound healing.