Noncanonical RGS14 structural determinants control hormone-sensitive NPT2A-mediated phosphate transport.

The sodium phosphate cotransporter-2A (NPT2A) mediates basal and parathyroid hormone (PTH)- and fibroblast growth factor-23 (FGF23)-regulated phosphate transport in proximal tubule cells of the kidney. Both basal and hormone-sensitive transport require sodium hydrogen exchanger regulatory factor-1 (NHERF1), a scaffold protein with tandem PDZ domains, PDZ1 and PDZ2. NPT2A binds to PDZ1.

Distinct and overlapping RGS14 and RGS12 actions regulate NPT2A-mediated phosphate transport.

Parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) control serum phosphate levels by downregulating the renal Na-phosphate transporter NPT2A, thereby decreasing phosphate absorption and augmenting urinary excretion. This mechanism requires NHERF1, a PDZ scaffold protein, and is governed by the regulator of G protein signaling-14 (RGS14), which harbors a carboxy-terminal PDZ ligand that binds NHERF1. RGS14 is part of a triad of structurally related RGS proteins that includes RGS12 and RGS10.

Functional Assessment of Cancer-Linked Mutations in Sensitive Regions of Regulators of G Protein Signaling Predicted by Three-Dimensional Missense Tolerance Ratio Analysis.

Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling by acting as negative regulators of G proteins. Genetic variants in RGS proteins are associated with many diseases, including cancers, although the impact of these mutations on protein function is uncertain. Here we analyze the RGS domains of 15 RGS protein family members using a novel bioinformatic tool that measures the missense tolerance ratio (MTR) using a three-dimensional (3D) structure (3DMTR).

RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein.

Phosphate homeostasis, mediated by dietary intake, renal absorption, and bone deposition, is incompletely understood because of the uncharacterized roles of numerous implicated protein factors. Here, we identified a novel role for one such element, regulator of G protein signaling 14 (RGS14), suggested by genome-wide association studies to associate with dysregulated Pi levels. We show that human RGS14 possesses a carboxy-terminal PDZ ligand required for sodium phosphate cotransporter 2a (NPT2A) and sodium hydrogen exchanger regulatory factor-1 (NHERF1)-mediated renal Pi transport.

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons.

The human genome contains vast genetic diversity as naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions.

The Ras-binding domain region of RGS14 regulates its functional interactions with heterotrimeric G proteins.

RGS14 is a 60 kDa protein that contains a regulator of G protein signaling (RGS) domain near its N-terminus, a central region containing a pair of tandem Ras-binding domains (RBD), and a GPSM (G protein signaling modulator) domain (a.k.a.

Activation of the regulator of G protein signaling 14-Gαi1-GDP signaling complex is regulated by resistance to inhibitors of cholinesterase-8A.

RGS14 is a brain scaffolding protein that integrates G protein and MAP kinase signaling pathways. Like other RGS proteins, RGS14 is a GTPase activating protein (GAP) that terminates Gαi/o signaling. Unlike other RGS proteins, RGS14 also contains a G protein regulatory (also known as GoLoco) domain that binds Gαi1/3-GDP in cells and in vitro.

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory.

Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus.

RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways.

MAPkinase signalling is essential for cell growth, differentiation and cell physiology. G proteins and tyrosine kinase receptors each modulate MAPkinase signalling through distinct pathways. We report here that RGS14 is an integrator of G protein and MAPKinase signalling pathways.

Unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other RGS R4/B subfamily members.

RGS2 and RGS5 are inhibitors of G-protein signaling belonging to the R4/B subfamily of RGS proteins. We here show that RGS2 is a much more potent attenuator of M1 muscarinic receptor signaling than RGS5. We hypothesize that this difference is mediated by variation in their ability to constitutively associate with the plasma membrane (PM).

Actively transcribed GAL genes can be physically linked to the nuclear pore by the SAGA chromatin modifying complex.

Recent work has demonstrated that some actively transcribed genes closely associate with nuclear pore complexes (NPC) at the nuclear periphery. The Saccharomyces cerevisiae Mlp1 and Mlp2 proteins are components of the inner nuclear basket of the nuclear pore that mediate interactions with these active genes. To investigate the physical link between the NPC and active loci, we identified proteins that interact with the carboxyl-terminal globular domain of Mlp1 by tandem affinity purification coupled with mass spectrometry.

RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling.

Protein kinase C interacting protein (PKCI-1) was identified among the potential interactors from a yeast two hybrid screen of human brain library using N terminal of RGSZ1 as a bait. The cysteine string region, unique to the RZ subfamily, contributes to the observed interaction because PKCI-1 interacted with N-terminus of RGS17 and GAIP, but not with that of RGS2 or RGS7 where cysteine string motif is absent. The interaction between RGSZ1 and PKCI-1 was confirmed by coimmunoprecipitation and immunofluorescence.

Selective interactions between Gi alpha1 and Gi alpha3 and the GoLoco/GPR domain of RGS14 influence its dynamic subcellular localization.

RGS14 is a multifunctional protein that contains an RGS domain, which binds active Gi/o alpha-GTP, a GoLoco/GPR domain, which binds inactive Gi alpha-GDP, and a tandem Rap1/2 binding domain (RBD). Studies were initiated to determine the roles of these domains and their interactions with Gi alpha on RGS14 subcellular localization. We report that RGS14 dynamic subcellular localization in HeLa cells depends on distinct domains and selective interactions with preferred Gi alpha isoforms.

Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop.

Regulators of G-protein signaling (RGS) proteins act directly on Galpha subunits to increase the rate of GTP hydrolysis and to terminate signaling. However, the mechanisms involved in determining their specificities of action in cells remain unclear. Recent evidence has raised the possibility that RGS proteins may interact directly with G-protein-coupled receptors to modulate their activity.

Novel activity of RGS14 on Goalpha and Gialpha nucleotide binding and hydrolysis distinct from its RGS domain and GDI activity.

The bifunctional protein RGS14 is both a GTPase activating protein (GAP) for Gialpha and Goalphaand a guanine nucleotide dissociation inhibitor (GDI) for Gialpha. This GDI activity is isolated to a region of the protein distinct from the RGS domain that contains an additional G protein-binding domain (RBD/GL). Here, we report that RGS14 missing its RGS domain (R14-RBD/GL) binds directly to Go and Gi to modulate nucleotide binding and hydrolysis by mechanisms distinct from its defined GDI activity.

RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling.

RGS proteins serve as GTPase-activating proteins and/or effector antagonists to modulate Galpha signaling events. In live cells, members of the B/R4 subfamily of RGS proteins selectively modulate G protein signaling depending on the associated receptor (GPCR). Here we examine whether GPCRs selectively recruit RGS proteins to modulate linked G protein signaling.

Phosphorylation of RGS14 by protein kinase A potentiates its activity toward G alpha i.

Regulators of G protein signaling (RGS proteins) modulate Galpha-directed signals because of the GTPase activating protein (GAP) activity of their conserved RGS domain. RGS14 and RGS12 are unique among RGS proteins in that they also regulate Galpha(i) signals because of the guanine nucleotide dissociation inhibitor (GDI) activity of a GoLoco motif near their carboxy-termini. Little is known about cellular regulation of RGS proteins, although several are phosphorylated in response to G-protein directed signals.