# Activation of the beta-3 integrins: Role of the Kindlins

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $511,647

## Abstract

Abstract
This proposal seeks to establish the role of kindlin-3 in physiological and pathophysiological responses.
Kindlin-3 (FERMT3) is one of the three member family of FERM domain intracellular adapter proteins, which
has >20 binding partners and thereby control numerous responses in numerous cells types. Our contributions
to the kindlin field have included the demonstration of their essential role in integrin activation; delineation of
the molecular basis for their interaction with integrin beta subunits; identification of a disease, LADIII,
associated with severe bleeding, compromised immunity, increased susceptibility to infections and
osteopetrosis arising from a deficiency of kindlin-3, demonstration of not only integrin dependent, but also
integrin independent functions of kindlins (e.g. perturbed hemostasis and vascular permeability); and the
implication of a central role of the kindlins in cancer biology. Adding to the importance of kindlin-3 is evidence
that it is not restricted to hematopoietic cells, but is present in and contributes to the biological responses of
endothelial cells and cancer cells, particularly to the progression and metastasis of breast cancer. Despite the
clear significance of kindlin-3 in vascular biology and pathology, it is this kindlin that has been particularly
resistant to analysis arising from the lack of cellular and in vivo models to understand the breadth of its
biological functions. We have resolved some of these barriers and are now poised to resolve key questions
regarding kindlin-3. We have developed assays and mouse strains in which the molecular basis of kindlin-3’s
function can be dissected. Specifically, we have in hand mouse strains in which the integrin-dependent and
independent responses can be distinguished (integrin binding site disabled) and tissue specific knockouts of
kindlin-3 to delete it from monocyte/macrophages and erythroid cells. We have also developed CRISPR/cas9
technology which has allowed us to knockout or replace kindlin-3 in cancer cells. Importantly, we have
identified a unique phosphorylation site in kindlin-3 that is not conserved in the other two kindlins, and have
shown that this post-translational event is of functional significance in hematopoietic and breast cancer cells
and distinguishes between kindlin-3 binding partners. Our specific aims are: 1) identify the role of integrin-
dependent and -independent functions in breast cancer progression and metastasis; 2) determine the
importance of phosphorylation of kindlin-3 in vascular and cancer cells; and 3) determine how kindlin-3
influences erythropoiesis and erythroid cell shape.
Overall, these studies will establish basic mechanisms by which kindlin-3 exerts its known functions, may
identify previously unappreciated functions of this molecule and may establish if kindlin-3 can serve as a
biomarker and as a therapeutic target.

## Key facts

- **NIH application ID:** 10136064
- **Project number:** 5R01HL096062-11
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** EDWARD Franklin PLOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $511,647
- **Award type:** 5
- **Project period:** 2009-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136064

## Citation

> US National Institutes of Health, RePORTER application 10136064, Activation of the beta-3 integrins: Role of the Kindlins (5R01HL096062-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136064. Licensed CC0.

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