Regulators of G protein signaling: role in hematopoiesis, megakaryopoiesis and platelet function

Abstract

Summary. Regulators of G protein signaling (RGS) are intracellular signaling regulators that bind activated G protein a subunits (Ga) and increase their intrinsic GTPase activity via their common RGS homology domain. In addition to their GTPase accelerating activity (GAP), RGS proteins also contain other domains that regulate their receptor selectivity, their interaction with other proteins such as adenylyl cyclase or their subcellular localization via interaction with scaffold proteins such as tubulin, 14-3-3 or spinophilin. There are at least 37 different RGS family members in humans and numerous physiological functions have been assigned to these proteins, which have rather a tissue-specific expression pattern. The role of some RGS proteins was shown to be important for hematopoiesis. More recent studies also focused on their expression in platelets, and for R4 RGS subfamily members RGS2, RGS16 and RGS18, it could be demonstrated that they regulate megakaryopoiesis and/or platelet function. These functional studies mostly comprised in vitro experiments and in vivo studies using small animal models. Their role in human pathology related to platelet dysfunction remains still largely unknown, except for a case report with a RGS2 gain of function mutation. In addition to an introduction on RGS signaling and different effectors with a special focus on the R4 subfamily members, we here will give an overview of the studies related to the role of RGS proteins in hematopoiesis, megakaryopoiesis and platelet function.

The regulator of G-protein signaling 18 regulates platelet aggregation, hemostasis and thrombosis

“…Regulators of G protein Signaling (RGS) play essential regulatory roles in the signaling of G protein-coupled receptors (GPCRs) and display remarkable specificity and selectivity in their regulation of GPCR-mediated physiological events [3,17,18]. To this end, RGS18 is a GTPase-activating protein for the G-aq and G-ai subunits of GPs, thereby it turns off signaling by GPCRs known to couple to these G proteins [7,8].…”

Plasma profiling reveals three proteins associated to amyotrophic lateral sclerosis

“…RGS proteins are known inhibitors of signal transduction and increase GTPase activity of the alpha subunits of G proteins 28. RGS18 expression has been reported in human platelets, leukocytes, megakaryocytes, and lymphocytes29–31 and it was found to decrease in abundance in degenerating muscle of rainbow trout 32.…”

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

“…RGS18 has been implicated in the control of osteoclastogenesis mediated by RANKL by modulating signaling through the proton sensing GPCR OGR1 (131). Several recent studies have documented a role for RGS18 in thrombopoiesis and platelet function (132–136). Following exposure to thrombin or thromboxane A2 RGS18 is phosphorylated on serine 49 and serine 218, which promotes its binding to 14-3-3 proteins leading to an inhibition of RGS18 GAP activity.…”