# Regulation of Hippo pathway signaling by mechanical forces

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $453,897

## Abstract

Project Summary
The long term goal of this project is to uncover the pathways by which the transcriptional co-activator
and oncogene YAP is regulated by the LATS and SRC kinases in response to mechanical stimuli,
which could lead to better treatments for cancer, and improved stem cell therapies. The terminal
Hippo pathway kinase LATS inhibits YAP nuclear localization, but also has a poorly characterized but
important functions in cytokinesis, whereas the SRC tyrosine kinase promotes YAP nuclear
localization. YAP nuclear localization is regulated by diverse stimuli such as the actin cytoskeleton,
substrate stiffness, cell detachment, cell crowding, and stretch to control density dependent inhibition
of growth, tissue repair and stem cell proliferation and differentiation. When in the nucleus, the YAP
promotes cell survival and proliferation. Here we will determine how LATS is regulated by both
tension at cell-cell junctions to control density dependent inhibition of cell growth and during mitosis to
control cytokinesis. Identification of specific mitotic pathways may allow LATS activity to be
manipulated to promote tissue regeneration without interfering with cell division. We will also test a
hypothesis for how the SRC kinase collaborates with the AMOT protein in response to cell adhesion
and other stimuli to target YAP to the nucleus. In Specific Aim 1, we will determine how several
proteins that comprise a tension sensor at cell-cell junctions work together to regulate LATS activity in
response to cellular tension across sheets of cells. In Specific Aim 2 we will test a hypothesis that
SRC turns AMOT from an inhibitor of YAP into an activator. Understanding this pathway will be
important for determining whether drugs that increase AMOT levels are appropriate therapies for a
given cancer. In Specific Aim 3 we will determine how LATS is activated in mitosis, the identity of its
mitotic substrates, and how it promotes cytokinesis. Overall this work will reveal how LATS and YAP
are regulated by specific stimuli. These studies will have an important impact on our understanding of
tumor suppression and tissue regeneration and may lead to better ways to manipulate these
important processes.

## Key facts

- **NIH application ID:** 10052161
- **Project number:** 2R01GM058406-22
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** DANNEL MCCOLLUM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,897
- **Award type:** 2
- **Project period:** 1998-03-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052161

## Citation

> US National Institutes of Health, RePORTER application 10052161, Regulation of Hippo pathway signaling by mechanical forces (2R01GM058406-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052161. Licensed CC0.

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