# Conformational regulation of TGF-β activation by integrin αvβ6

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $783,795

## Abstract

Summary/Abstract: TGF-b is a key driver of lung fibrosis. The long-term goal of our research is to acquire a
deep understanding of the regulation of TGF-b activity to develop new strategies and treatments for fibrosing
lung disease. Currently, there are no effective therapies to treat lung fibrosis. The multifunctional cytokine TGF-
b is a potent mediator of fibrosis and is a potential therapeutic target in fibrosing lung disease. However,
targeting TGF-b itself or its receptors is associated with demonstrated risks as evidenced by toxicities in
rodents, primates and humans. More selective targeting of the fibroinflammatory effects of TGF-b, without
perturbing its normal essential functions are highly desirable. One property of TGF-b that may allow more
selective targeting is to target its “activation” since it is always produced in a latent form (L-TGF-b) that requires
activation in order to function. Another feature of L-TGF-b that could facilitate more specific targeting is to that
it is normally covalently bound to the extracellular matrix or to the surface of cells by association with TGF-b
binding proteins such as latent-TGF-b binding protein (LTBP) or glycoprotein-A repetitions predominant
(GARP). We and others have shown that L-TGF-b binding to two integrins, a 8 and a
vb
vb
6 is essential for
TGF-b activation in vivo. For the integrin a 6 activation mechanism, it has long been assumed that TGF-b
vb
must be released from LAP so that free TGF-b can diffuse and bind its receptors on target cells. The structural
mechanism for such release of TGF-b is incompletely understood since full-length a
vb
6 has not been studied
in complex with TGF-b bound to TGF-b binding proteins. Based on recent structural data obtained using single
particle electron cryomicroscopy (cryo-EM), we have recently proposed a new model whereby a
vb
8 can bind
to L-TGF-b on cells presenting the L-TGF-b/GARP complex and induce signaling without release and diffusion
of TGF-b. These two different models of TGF-b activation may be able to be separately targeted, which could
help mitigate therapeutic risk. Here in four aims, we will employ a structure-based approach to address the
mechanism of a
vb
6-mediated TGF-b activation. We will use the technique of electron cryomicroscopy (cryo-
EM), which is a technique that allows for high-resolution structures of proteins and protein complexes in
physiologically relevant conditions. Cryo-EM will be used to examine the role of integrin a
vb
6 conformation in
the mechanism of TGF-b activation. These studies will improve mechanistic understanding of TGF-b activation
and therapeutic targeting strategies to more selectively and safely inhibit it.

## Key facts

- **NIH application ID:** 10863879
- **Project number:** 5R01HL165175-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Yifan Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $783,795
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863879

## Citation

> US National Institutes of Health, RePORTER application 10863879, Conformational regulation of TGF-β activation by integrin αvβ6 (5R01HL165175-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10863879. Licensed CC0.

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