# RGS14 Regulation of Hormone-sensitive NPT2A-mediated Phosphate Transport

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $465,422

## Abstract

PROJECT SUMMARY: PTH and FGF23 initiate signaling pathways in renal proximal tubule cells that converge
on the [NPT2A:NHERF1] complex to inhibit phosphate uptake. Mice lacking the PDZ protein NHERF1 and
humans harboring NHERF1 mutations are hypophosphatemic. Important gaps exist in understanding the
elements involved in these actions due to unidentified factors. Numerous GWAS studies of patients with chronic
kidney disease implicate RGS14, which harbors a PDZ-recognition motif. We propose that RGS14 is a novel
regulator of hormone-sensitive phosphate transport, and provide preliminary data to support this idea. RGS14
is scaffold that integrates G protein, MAPK, and Ca++/CaM signaling pathways. Its actions are best understood
in rodent brain, where RGS14 suppresses synaptic plasticity and hippocampal-based learning. Nothing is known
about RGS14 effects on hormone action or in kidney. Our preliminary findings show that RGS14 suppresses
both PTH- and FGF23-regulated phosphate transport. RGS14 persistently attenuates PTH-regulated phosphate
transport in primary human proximal tubule cells. RGS14 knock-down by siRNA reverses this action to reveal
full PTH activity. RGS14 add-back to cells lacking the protein blocks PTH actions. Human RGS14 contains a C-
terminal PDZ ligand (-DSAL) that directly binds NHERF1. Mutations in the PDZ-ligand disrupt RGS14 binding
to NHERF1 and interfere with RGS14 regulation of hormone actions. These findings identify RGS14 as an
entirely new element regulating hormone action on a vital homeostatic activity, and raise the hypothesis that
RGS14 is a novel regulator of hormone-sensitive [NPT2A:NHERF1]-mediated phosphate transport in renal proximal
tubule cells. Three Aims will test this premise. AIM 1 will define how RGS14 regulates assembly, disassembly of
[NPT2A:NHERF1], its internalization and hormone-sensitive phosphate uptake. AIM 2 will define the locus of
RGS14 effects on PTH and FGF23 signaling and the impact of hormone-directed NHERF1 phosphorylation on
RGS14 regulation of the [NPT2A:NHERF1] complex. AIM 3: will define how PTH- and FGF23-directed signaling
affect RGS14 interactions with NHERF1 and the [NHERF1:NPT2A] complex. These studies will identify novel
roles and molecular mechanisms by which RGS14 regulates NPT2A function and hormone-sensitive phosphate
transport in kidney as related to kidney disease.

## Key facts

- **NIH application ID:** 10317557
- **Project number:** 1R01GM140632-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Peter A Friedman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $465,422
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317557

## Citation

> US National Institutes of Health, RePORTER application 10317557, RGS14 Regulation of Hormone-sensitive NPT2A-mediated Phosphate Transport (1R01GM140632-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317557. Licensed CC0.

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