# Structural mechanism of integrin-mediated TGF-b activation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $737,918

## Abstract

Summary/Abstract: TGF-Beta drives the fibroinflammatory processes that leads to lung and airway fibrosis. The
long-term goal of this project is to acquire a deep understanding of the regulation of TGF-Beta activity to develop
new strategies and treatments for fibrosing lung disease. There are few effective therapies to treat chronic
fibrosing and inflammatory diseases of the lung. The cytokine TGF-Beta is a central mediator of fibrosis and
pathologic inflammation and is a potential therapeutic target in fibrosing lung disease. However, the practical
utility of targeting TGF-Beta itself or its receptors is limited by risk of toxicities seen in rodents, primates and
humans. More specific methods to target the fibroinflammatory effects of TGF-Beta are highly desirable. A
promising method to more specifically target local effects of TGF-Beta is to target its “activation” since it is always
produced in a latent form (L-TGF-Beta) that must be activated in order to function. Another feature of L-TGF-Beta that
could facilitate more specific targeting is that it is covalently bound to specific cell surfaces by GARP. L-TGF-Beta
binding to the integrin alphavBeta8 is essential for TGF-Beta activation in vivo. For the alphavBeta8 activation mechanism, as
well as all others, it has long been assumed that TGF-Beta must be released from LAP so that free TGF-Beta can
diffuse and bind its receptors on target cells. Based on recent structural data obtained using single particle
electron cryomicroscopy (cryo-EM), we have recently proposed a new model whereby alphavBeta8 can bind to L-TGF-Beta on cells presenting the L-TGF-Beta/GARP complex and induce signaling without release and diffusion of
TGF-Beta. Here in three aims, we address three critical questions concerning this new model of L-TGF-Beta
activation. (1) Which flexible domains of L-TGF-Beta of the alphavBeta8/L-TGF-Beta/GARP ternary complex shield TGF-Beta
from its receptors? (2) Is flexibility of L-TGF-Beta induced by binding to alphavBeta8 necessary to mediate TGF-Beta
activation? (3) Do TGF-Beta receptors (TGF-BetaRs) bind to TGF-Beta within the alphavBeta8/L-TGF-Beta/GARP complex? To
answer these questions, we will use cryo-EM to determine the structure of the alphavBeta8/L-TGF-Beta/GARP complex
to determine how flexibility of L-TGF-Beta contributes to TGF-Beta activation, and finally we will capture the
multimeric complex of TGF-BetaRs with alphavBeta8/LTGF-Beta/GARP. These studies will improve mechanistic
understanding of TGF-Beta activation and therapeutic targeting strategies to inhibit it.

## Key facts

- **NIH application ID:** 10407522
- **Project number:** 5R01HL134183-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Yifan Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $737,918
- **Award type:** 5
- **Project period:** 2016-07-04 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407522

## Citation

> US National Institutes of Health, RePORTER application 10407522, Structural mechanism of integrin-mediated TGF-b activation (5R01HL134183-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10407522. Licensed CC0.

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