# WNK and TGF-beta in Endothelial Migration

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $405,000

## Abstract

Abstract
The long term goal of this research is to determine the molecular mechanisms underlying the interactions
of WNK1 with TGFβ signaling on endothelial plasticity and homeostasis. Failed angiogenesis in
endothelial-specific WNK1 null mice led to embryonic death. We have found two processes important for
endothelial plasticity that are coordinately regulated by TGFβ and WNK1: conversion of cells to a migratory
phenotype and tight junction breakdown that occurs with complete endothelial-mesenchymal transition.
These processes contribute to normal vascular physiology and to pathophysiology. We will investigate
how signaling pathways regulated by TGFβ and WNK1 intersect in controlling endothelial cell behavior and
characteristics. WNK-selective kinase inhibitors, protein depletion, gene editing, proximity ligation, gene
expression and other biochemical means will be used in cell- and tissue-based assays to discover the
mechanisms through which WNK1 mediates dynamic reorganization of endothelial cell structures
underlying normal and pathophysiological angiogenesis in tandem with TGFβ. In the first specific aim, we
will determine interactions between TGFβ and WNK1 signaling pathways that regulate expression of the
mesenchymal transcription factor Slug (Snai2) and subsequent induction of endothelial cell motility. We
hypothesize that WNK1 activates Slug expression and migration through actions on TGFβ-regulated
SMADs. Slug promotes endothelial cell migration and remodeling by inducing proteins that repress
cell-cell adhesion and enhance a migratory mesenchymal phenotype. In the second specific aim, we will
determine how WNK1 promotes TGFβ-induced tight junction disassembly. In response to TGFβ, the
WNK1 substrate kinase OSR1 binds to tight junction proteins along with other signaling proteins and TGFβ
receptors to break down tight junctions. Inhibiting WNK1 kinase activity prevents co-immunoprecipitation
of OSR1 with occludin and prevents TGFβ-induced tight junction disassembly in endothelial cells. We
hypothesize that WNK1 is required for TGFβ-induced tight junction disassembly through actions of its
substrate kinase OSR1. We will analyze how WNK1/OSR1 participate in TGFβ-initiated tight junction
break down to discover the steps requiring their cooperation. We will identify components in
OSR1-occludin complexes and the effects of interfering with OSR1 function on tight junction breakdown.
Essential events will be established using rescue strategies. Our results will define the extent of
cooperation between TGFβ and WNK1 signaling mechanisms and uncover opportunities for therapeutic
targeting of the WNK1 pathway in disease. Our findings will lead to a better understanding of normal and
pathological angiogenesis.

## Key facts

- **NIH application ID:** 10146471
- **Project number:** 5R01HL147661-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** MELANIE H. COBB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146471

## Citation

> US National Institutes of Health, RePORTER application 10146471, WNK and TGF-beta in Endothelial Migration (5R01HL147661-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10146471. Licensed CC0.

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