# Novel Regulatory Mechanisms Underlying Inside-out Integrin Activation

> **NIH NIH R35** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $467,500

## Abstract

Project Summary/Abstract
 Integrins play important roles in basic cellular functions such as adhesion, growth, and migration as well
as specialized functions in platelet plug formation during hemostasis and in T cell mediated immune
responses. Abnormal expression and hyperactivity of integrins leads to cardiovascular diseases, impaired
inflammatory responses, T cell malfunction, and enhanced tumor metastasis. Current integrin inhibitors that
block extracellular ligand binding often cause serious adverse effects. Our overall goal is to elucidate the
molecular mechanisms that activate integrins more specifically through the inside-out signaling pathway, thus
facilitating the development of new therapies targeting this pathway. The main focus of this proposed study is
to understand the structural basis of intermolecular interactions and intramolecular rearrangements that
modulate integrin activity, thus altering cell adhesion and motility.
 The inside-out integrin signaling pathway has recently emerged as a new target for suppressing integrin
activity. Integrin activation through this pathway is triggered by talin and mediated by a small GTPase, Rap1,
and its effector protein RIAM (Rap1-interacting adaptor molecule). A co-activator, kindlin, also significantly
enhanced the integrin activity. However, many key questions regarding how specific inter- and intra-molecular
interactions regulate inside-out integrin activation remain unanswered.
 We have previously determined the structural basis of RIAM recruitment by Rap1 and the PM
translocation and conformational activation of talin by RIAM. In this proposal, we aim to address the following
central questions regarding the conformational rearrangement and specific interactions underlying the
functional regulation of RIAM, talin, and kindlin: 1) to elucidate the structural basis of regulatory intramolecular
interactions of RIAM and talin; 2) to determine the molecular basis of enhanced talin activity induced by the
interaction of RIAM and talin; and 3) to probe the molecular mechanisms underlying the different integrin-
regulating properties among kindlin isoforms and the co-localization of kindlin and talin in integrin signaling.
Our studies will significantly advance the understanding of the regulatory mechanisms of integrin activation
through the inside-out pathway.

## Key facts

- **NIH application ID:** 9983750
- **Project number:** 5R35GM119560-05
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Jinhua Wu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,500
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983750

## Citation

> US National Institutes of Health, RePORTER application 9983750, Novel Regulatory Mechanisms Underlying Inside-out Integrin Activation (5R35GM119560-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983750. Licensed CC0.

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