A role for Regulator of G protein Signaling-12 (RGS12) in the balance between myoblast proliferation and differentiation

Abstract

Regulators of G Protein Signaling (RGS proteins) inhibit G protein-coupled receptor (GPCR) signaling by accelerating the GTP hydrolysis rate of activated Gα subunits. Some RGS proteins exert additional signal modulatory functions, and RGS12 is one such protein, with five additional, functional domains: a PDZ domain, a phosphotyrosine-binding domain, two Ras-binding domains, and a Gα·GDP-binding GoLoco motif. RGS12 expression is temporospatially regulated in developing mouse embryos, with notable expression in somites and developing skeletal muscle. We therefore examined whether RGS12 is involved in the skeletal muscle myogenic program. In the adult mouse, RGS12 is expressed in the tibialis anterior (TA) muscle, and its expression is increased early after cardiotoxin-induced injury, suggesting a role in muscle regeneration. Consistent with a potential role in coordinating myogenic signals, RGS12 is also expressed in primary myoblasts; as these cells undergo differentiation and fusion into myotubes, RGS12 protein abundance is reduced. Myoblasts isolated from mice lacking Rgs12 expression have an impaired ability to differentiate into myotubes ex vivo , suggesting that RGS12 may play a role as a modulator/switch for differentiation. We also assessed the muscle regenerative capacity of mice conditionally deficient in skeletal muscle Rgs12 expression (via Pax7 -driven Cre recombinase expression), following cardiotoxin-induced damage to the TA muscle. Eight days post-damage, mice lacking RGS12 in skeletal muscle had attenuated repair of muscle fibers. However, when mice lacking skeletal muscle expression of Rgs12 were cross-bred with mdx mice (a model of human Duchenne muscular dystrophy), no increase in muscle degeneration was observed over time. These data support the hypothesis that RGS12 plays a role in coordinating signals during the myogenic program in select circumstances, but loss of the protein may be compensated for within model syndromes of prolonged bouts of muscle damage and repair.

RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis

“…Interestingly, the PTB domain of RGS12 is unique, which does not contain any of the conserved for phosphotyrosine coordination (Uhlik et al, 2005). Most recently, Schroer et al reported that the RGS12 PTB domain binds to the specific phosphoinositides and then is localized to early endosomes in cultured myoblasts (Schroer et al, 2019;Willard et al, 2007). Here, we found that the PTB domain is essential for association of RGS12 and NF-kB(p65) to further promote the NF-kB(p65) activation.…”

“…Regulator of G Protein Signaling 12 (RGS12) was first found as the largest protein in the RGS family (Snow et al, 1997). Further studies found that RGS12 is located in both the cytosol and the nucleus (Willard et al, 2007) and contains an N-terminal PDZ (PSD-95, disc-large, zo-1) domain, PTB (phosphotyrosine binding) domain, RGS domain, tandem RAS-binding domain (RBD), and a GoLoco (Gai/o-Loco) interaction motif, which play important roles through binding different proteins (Snow et al, 1998;Ponting, 1999;Siderovski et al, 1999;Kimple et al, 2001). RGS12 is involved in multiple signaling pathways, including G protein-coupled receptors (GPCRs) (Kimple et al, 2001), receptor tyrosine kinases (RTKs) (Willard et al, 2007), Ras GTPases (Snow et al, 1998;Willard et al, 2007), and MEK1/2-ERK1/2 coordinated signaling (Huang et al, 2016).…”

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

“…RGS12 is thus ideally placed to integrate GNAI and other signaling pathways (40). RGS12 was implicated previously in cell differentiation including myogenesis, neurogenesis, and bone formation (39,(41)(42)(43)(44)(45). The Drosophila RGS12 homolog Loco regulates oriented cell division with the GPSM2 homolog Pins (46), but the RGS12 protein is not known to be polarized or to affect HC differentiation.…”

Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination

“… 20 As the largest RGS protein, RGS12 involves in several signaling pathways such as receptor tyrosine kinases (RTKs), mitogen-activated protein kinases (MAPKs), G protein-coupled receptors (GPCRs), and Ras GTPases. 22 , 23 Moreover, RGS12 regulates post-modifications of multiple proteins under physiological and pathological conditions. 24 However, whether RGS12 regulates inflammatory diseases like OA through controlling the ubiquitination of component(s) in NF-κB is still unclear.…”