# Regulation of WNK signaling by potassium and Mo25: structure, function and physiology

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $474,831

## Abstract

Mutations in human WNK (With No Lysine) kinases are associated with hyperkalemia, hypertension and chronic
kidney disease. However, despite extensive characterization of (patho)physiological roles of WNKs in the kidney
and extrarenal tissues, there is surprisingly little understanding of how WNKs themselves are regulated. WNKs
regulate epithelial ion transport in the mammalian kidney. The applicants’ long-term goal is to achieve
mechanistic understanding of epithelial ion transport mechanisms relevant to human kidney function. Chloride
ion is known to regulate WNKs. The overall objective of this application is to define and understand new
mechanisms of WNK regulation. This renewal application builds on three significant advances from the currently
funded grant. First, potassium inhibits Drosophila and mammalian WNKs through chloride-independent
mechanisms. Second, the scaffold protein Mo25 (Mouse protein 25/Cab39) is an important regulator of WNK
signaling, and activates WNKs independent of its known effects on SPAK (Ste20-related proline alanine rich
kinase) and OSR1 (oxidative stress response) kinases. Third, potassium and Mo25 have differential effects on
the kidney-expressed mammalian WNKs 1, 3 and 4. The central hypothesis is that potassium and Mo25 directly
regulate WNK kinase activity, with differential effects on mammalian WNK isoforms. Guided by strong preliminary
data, the central hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism and
physiological consequences of WNK regulation by potassium; 2) Elucidate novel mechanisms of Mo25 regulation
of WNK signaling; and 3) Determine the molecular basis for differential WNK isoform regulation by potassium
and Mo25. The approach is innovative by leveraging insights from biophysical and structural studies to determine
molecular mechanisms of epithelial ion transport regulation, using a unique platform, the Drosophila Malpighian
tubule, that has powerful molecular genetic tools and tractable physiologic readouts. Assays have been
established, and demonstrated feasible in the investigators’ hands, to: 1) identify WNK potassium binding sites,
generate potassium-insensitive WNK mutants, and test their effects on transepithelial ion transport; 2) determine
how Mo25 regulates WNK activity in vitro and in the tubule, and probe the interactions between Mo25, potassium
and chloride in WNK regulation; and 3) test differences in potassium and Mo25 regulation of WNKs 1, 3 and 4.
Successful completion of the proposed studies will elucidate the most comprehensive mechanistic understanding
of WNK regulation achieved to date. This is significant, because delineation of the importance of these WNK
regulatory mechanisms in various (patho)physiological contexts, together with the molecular insights gained from
the studies proposed here, will allow the development of targeted approaches to therapeutically modulate WNK
signaling. This has translational impact in a broad range of cond...

## Key facts

- **NIH application ID:** 10298458
- **Project number:** 2R01DK110358-07A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** AYLIN RACHEL RODAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,831
- **Award type:** 2
- **Project period:** 2016-09-13 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298458

## Citation

> US National Institutes of Health, RePORTER application 10298458, Regulation of WNK signaling by potassium and Mo25: structure, function and physiology (2R01DK110358-07A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10298458. Licensed CC0.

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