# Regulation of calcium signaling by the PKD2 gene product

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $329,856

## Abstract

Naturally occurring mutations in two separate genes, PKD1 and PKD2, are responsible for the vast majority
(~99%) of all cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common
genetic diseases affecting 1 in 1000 Americans. The hallmark of ADPKD is the development of epithelial cysts
in the kidney, liver, and pancreas. Currently, there is no effective treatment for ADPKD. PKD1 encodes a large
plasma membrane protein (PKD1 or Polycystin 1) with a long extracellular domain and has been speculated
that it can function as an atypical G protein coupled receptor. PKD2 encodes an ion channel of the Transient
Receptor Potential superfamily (TRPP2, PKD2, or Polycystin 2). However, the molecular function of these
proteins and the mechanism(s) by which mutations in PKD1 and PKD2 cause ADPKD have been elusive. We
have shown recently that PKD1 and TRPP2 form a complex at the plasma membrane that is activated by
secreted WNT ligands. WNT proteins bind directly to the extracellular domain of PKD1 and induce Ca2+ influx
and whole cell currents that are dependent on TRPP2. The PKD1/TRPP2 complex contains Dishevelleds
(DVLs), which are cytoplasmic proteins that mediate Wnt signaling. The PKD1/TRPP2 complex has an
essential role in directed cell migration and chemotaxis in response to a WNT ligand. In frog embryos pkd1
works together with wnt9a and dvl2 to control kidney tubular diameter. Therefore, we hypothesize that PKD1
and TRPP2 mediate WNT-induced Ca2+ signaling that is essential for directed cell migration and contributes to
the determination of kidney tubule diameter. In this proposal, we will determine the mechanism of WNT-
induced activation of PKD1/TRPP2 (Specific Aim 1). Determine the step(s) in WNT-induced directed cell
migration specifically affected by PKD1 and TRPP2 (Specific Aim 2). Determine whether DVLs alone or in
association with other cytosolic proteins linked to Wnt signaling function downstream of PKD1 and TRPP2 in
WNT-induced cell migration (Specific Aim 3). This proposal is expected to shed light onto the mechanisms of
WNT-induced activation of the PKD1/TRPP2, the mechanisms by which these proteins regulate directed cell
migration, and cellular pathways activated immediately downstream of WNT-induced PKD1/TRPP2-mediated
Ca2+ signaling. Knowledge of these pathways can be used as the springboard for the discovery of new
druggable targets for ADPKD.

## Key facts

- **NIH application ID:** 9927634
- **Project number:** 5R01DK059599-16
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Leonidas Tsiokas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,856
- **Award type:** 5
- **Project period:** 2017-06-26 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927634

## Citation

> US National Institutes of Health, RePORTER application 9927634, Regulation of calcium signaling by the PKD2 gene product (5R01DK059599-16). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9927634. Licensed CC0.

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