# Structural mechanism of integrin-mediated TGF-b activation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $737,537

## Abstract

Summary/Abstract: TGF- 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- 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- 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- 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- are highly desirable. A
promising method to more specifically target local effects of TGF- is to target its “activation” since it is always
produced in a latent form (L-TGF-) that must be activated in order to function. Another feature of L-TGF- that
could facilitate more specific targeting is that it is covalently bound to specific cell surfaces by GARP. L-TGF-
binding to the integrin v8 is essential for TGF- activation in vivo. For the v8 activation mechanism, as
well as all others, it has long been assumed that TGF- must be released from LAP so that free TGF- 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 v8 can bind to L-
TGF- on cells presenting the L-TGF-/GARP complex and induce signaling without release and diffusion of
TGF-. Here in three aims, we address three critical questions concerning this new model of L-TGF-
activation. (1) Which flexible domains of L-TGF- of the v8/L-TGF-/GARP ternary complex shield TGF-
from its receptors? (2) Is flexibility of L-TGF- induced by binding to v8 necessary to mediate TGF-
activation? (3) Do TGF- receptors (TGF-Rs) bind to TGF- within the v8/L-TGF-/GARP complex? To
answer these questions, we will use cryo-EM to determine the structure of the v8/L-TGF-/GARP complex
to determine how flexibility of L-TGF- contributes to TGF- activation, and finally we will capture the
multimeric complex of TGF-Rs with v8/LTGF-/GARP. These studies will improve mechanistic
understanding of TGF- activation and therapeutic targeting strategies to inhibit it.

## Key facts

- **NIH application ID:** 10073295
- **Project number:** 2R01HL134183-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Yifan Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $737,537
- **Award type:** 2
- **Project period:** 2016-07-04 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073295

## Citation

> US National Institutes of Health, RePORTER application 10073295, Structural mechanism of integrin-mediated TGF-b activation (2R01HL134183-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10073295. Licensed CC0.

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