Related Experiment Video
Updated: Jun 3, 2025
08:45
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
6.2K
Noncanonical RGS14 structural determinants control hormone-sensitive NPT2A-mediated phosphate transport
W Bruce Sneddon1, Suneela Ramineni2, G Emme Van Doorn2
1Laboratory for GPCR Biology, Departments of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
The Biochemical Journal
|January 10, 2025
Summary
Regulator of G protein signaling 14 (RGS14) controls kidney phosphate transport by binding to NHERF1. Specific phosphorylation sites on RGS14 are crucial for regulating phosphate transport in response to PTH and FGF23.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Sodium phosphate cotransporter-2A (NPT2A) is vital for kidney phosphate reabsorption.
- NPT2A function is regulated by parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23).
- Sodium hydrogen exchanger regulatory factor-1 (NHERF1) scaffold protein is essential for NPT2A activity.
Purpose of the Study:
- To elucidate the structural elements of RGS14 responsible for regulating PTH- and FGF23-sensitive phosphate transport.
- To identify the specific mechanisms by which RGS14 modulates hormone action on NPT2A.
Main Methods:
- Utilized RGS14 truncation and point mutants to assess functional domains.
- Investigated the role of specific serine residues (Ser266, Ser269) in RGS14 function via alanine substitution.
- Analyzed phosphorylation of RGS14 and peptide constructs in response to PTH and FGF23 stimulation.
Main Results:
- RGS14 regulates NPT2A-mediated phosphate transport by interacting with NHERF1.
- Truncation of RGS14's N-terminal or RGS domain did not abolish function, but removal of the linker sequence did.
- Phosphorylation of Ser266 and Ser269 within the RGS14 linker region is essential for its regulatory activity on hormone-sensitive phosphate transport.
Conclusions:
- RGS14 acts as a critical regulator of kidney phosphate homeostasis.
- Targeted phosphorylation of RGS14 at Ser266 and Ser269 is a key mechanism for mediating the effects of PTH and FGF23 on phosphate transport.
- An intact PDZ ligand interaction and specific linker phosphorylation are required for RGS14's regulatory function.
Related Concept Videos
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.3K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.3K
01:45Regulation of Nuclear Protein Sorting
2.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.4K
01:11IP3/DAG Signaling Pathway
11.9K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
11.9K
02:54Protein Kinases and Phosphatases
13.0K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.0K
01:09GPCRs Regulate Adenylyl Cylase Activity
5.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.3K
01:22Activation and Inactivation of G Proteins
6.7K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.7K