Integrazione temporale del segnale mediato da recettori accoppiati a proteine G: il potenziale ruolo di G15 nella cancerogenesi

G15 is a heterotrimeric G protein of the Gq/11 family. In this study, we describe its exceptional poor sensitivity to the general regulatory mechanism of G protein-coupled receptor (GPCR) desensitization. Enhancing β2 adrenergic receptor desensitization by arrestin overexpression, did not affect signalling to G15. Similarly, increased levels of arrestin did not affect G15 signalling triggered by the activation of V2 vasopressin and δ opioid receptors. Furthermore, co-immunoprecipitation experiments showed that G15 α subunit (as opposed to Gαq and Gαs) is recruited to a V2 vasopressin receptor mutant that is constitutively desensitized by β-arrestin. Interestingly, co-expression of G15 partially rescued cell surface localization and signalling capabilities of the same mutant and supported its sustained activity on downstream effectors including PKD1. However, differential modulation by the agonist was observed while comparing effectors activity to receptor internalization. Taken together, these findings provide evidence for a novel mechanism whereby GPCR desensitization can be bypassed and G15 can support sustained signalling in cells chronically exposed to hormones or neurotransmitters. This aspect led us to hypothesize that G15 presence could be associated to poorly regulated physiological states, and in particular with tumor formation. A screening demonstrated Gα15 presence in 10 out of 40 human cancer cell lines analyzed, all derived from a variety of tissues reported as negative. Gα15 mRNA and protein were also found in pancreatic and prostate tumor biopsies. Notably, Gα15 was present in the proliferating fraction of the tumor as demonstrated by xenotransplantation of the tumors in nude mice.