# Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology

> **NIH NIH R35** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $783,287

## Abstract

Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology.
Classical cadherins are cell-cell adhesion proteins that regulate tissue morphogenesis and cell junctions during
physiological processes. They are highly regulated at the cell surface, controlling dynamic interactions between
cells. Although much is known about the basic functions of cadherin-mediated adhesion, an understanding of
the mechanisms underlying dynamic cell surface regulation, has not yet been achieved, nor is it well
understood how such regulatory mechanism control physiological processes in vivo. Cadherins also transduce
signals into the cell to convey information about the state of the tissue. One way they do is by stimulation of the
Hippo-YAP signaling pathway to mediate contact inhibition of growth. This process is antagonized by growth
factor signaling, via the PI3-kinase (PI3K) signaling pathway, which inhibits the Hippo pathway and stimulates
nuclear YAP. We will investigate the mechanisms underlying the regulation of cadherin homophilic adhesive
binding at different levels of analysis, from basic biochemical/biophysical/structural mechanisms, through cell
biological process controlling adhesion (especially the role of p120-catenin), to evaluating the roles of adhesion
regulation in physiological processes in vivo. We've found that cancer- and cleft lip-associated mutations in E-
cadherin specifically interfere with the regulation of adhesion at the cell surface, and these will provide valuable
tools for these studies. In vivo studies of cadherin regulation will focus on their roles in physiological control of
barrier function in both epithelia and endothelia, especially during inflammatory processes where control of
these functions are especially important. Studies on endothelial junctional regulation will require us to develop
tools for studying VE-cadherin regulation, including activating antibodies, and models for endothelial barrier
function; these will be compared to our studies of E-cadherin in epithelia. We'll also investigate the
mechanisms by which cadherins transduce various signals into the cell. A major focus will be on the regulation
of the Hippo-YAP pathway and associated TEAD transcription factors by cadherin-mediated contact and by
growth factors and PI3K signaling. The goals are both to understand how they function and to enable us to
develop genetic approaches to selectively perturb these interactions in vivo to evaluate their importance. Hippo
signaling by formation of cadherin contacts will be compared to signaling by tight junctions as well as signals
produced by mechanical tension at the cadherins. The Hippo-YAP pathway may be an important new branch
of the PI3K signaling pathway that regulates tissue growth in addition to the well-known Akt-TOR pathways.
This hypothesis will be tested in vivo both by studies on tissue overgrowth diseases caused by somatic mosaic
constitutively active PI3K mutations an...

## Key facts

- **NIH application ID:** 10135997
- **Project number:** 5R35GM122467-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** BARRY M. GUMBINER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $783,287
- **Award type:** 5
- **Project period:** 2017-08-04 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135997

## Citation

> US National Institutes of Health, RePORTER application 10135997, Regulation of cell junctions and cell contact dependent signaling in tissue development and physiology (5R35GM122467-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135997. Licensed CC0.

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