The puzzling uniqueness of the heterotrimeric G15 protein and its potential beyond hematopoiesis

Heterotrimeric G proteins transduce the signals of the largest family of membrane receptors (G protein-coupled receptors, GPCR) hence triggering the activation of a wide variety of physiological responses. G15 is a G protein characterized by a number of functional peculiarities that make its signalling exceptional: - it can couple to a variety of Gs-, Gi/o-, Gq-linked receptors to PLC activation; - relatively to other G-proteins it is poorly affected by β-arrestin-dependent desensitization, the general mechanism that regulates GPCR function; - its expression is detected at the protein level only in highly specific cell types (hematopoietic and epithelial cells). The G15 {alpha} subunit displays unique structural and biochemical properties and is phylogenetically the most recent and divergent component of the G{alpha}q/11 subfamily. All these aspects shed a mysterious light on the biological role of this protein, which remains substantially elusive. Thus far, G15 signalling has been analyzed in the context of hematopoiesis. Here, we highlight observations supporting the view that G15 functions may extend further beyond the immune system. In addition, we describe puzzling aspects of G15 signalling that offer a novel perspective in the understanding of its physiological role.