- Associate Professor, Department of Medicine
- Associate Professor, Department of Cell Biology
- Co-Director Honors Program
- American Board of Internal Medicine (Critical Care Medicine)
- American Board of Internal Medicine (Pulmonary Disease)
- American Board of Internal Medicine - Internal Medicine
Education and Training
- Fellowship, Brigham & Womens Hospital, Pulmonary, Crit Care
- MD from Washington University
How integrins activate latent TGF1 and TGF3 during development and in disease.Our lab studies how latent forms of TGF are activated by integrins in vivo.
TGF is a ubiquitously produced growth factor with important roles in pathologic processes such as cancer, fibrosis and autoimmunity, and in normal development, wound repair and homeostasis. There are three TGF isoforms, and all are secreted in a latent form. Latency is the result of a noncovalent association of the growth factor with its propeptide, which is called latency-associate peptide (LAP). TGF must be released from LAP before it can bind TGF receptors. The activation step is highly regulated but the specific activation mechanisms involved vivo have been poorly understood.
We discovered that v6, a cell surface adhesion molecule in the integrin family, can activate latent TGF1 and TGF3 by interacting with an RGD sequence in the TGF1 and TGF3 LAPs. v6 is expressed in epithelia, particularly after injury. Mice lacking v6 have lung inflammation and are protected from lung fibrosis due to a relative lack of TGF signaling in the lung.
We also collaborated with S. Nishimura's lab at UCSF to show that a second RGD-binding integrin, v8, activates TGF1 and TGF3. Mice lacking this integrin have abnormalities in vascular development. Comparison of knockouts of the two TGFs and the two integrin subunits reveals several partially or completely overlapping abnormalities in palate closure, immune regulation, and vascular development, suggesting that v6 and v8 are key TGF1/3 activators in vivo.
To determine the role of all RGD-binding integrins in the activation of latent TGF1, we made mice with a knock-in mutation of the TGF1 gene that changes the RGD site to RGE. These mice produce normal amounts of latent TGF1, but it cannot be activated by RGD-binding integrins. Strikingly, the mice have the same abnormalities seen in TGF1-null mice, indicating that RGD-binding integrins are indispensable for TGF1 activation.
We are currently further exploring the connection between these two integrins and the two RGD-containing TGF isoforms by generating mice with combined TGF1/3 mutations and mice with combined v6/v8 deficits. Our results support a tight functional system involving the two TGFs and the two activating integrins. For example, mice with combined v6/v8 deficits have completely penetrant cleft palate, and mice with combined TGF1/3 mutations have the CNS vascular changes seen in v8-null mice.
We are now focusing on the immune phenotype of mice lacking function of both v6 and v8. These mice develop severe autoimmune reactions that appear identical to (if not more severe than) those of TGF1-null mice. Also, we are testing the effectiveness of an inhibitory anti-v6 mAb, developed by Biogen Idec, in mouse models of lung fibrosis. We find that anti-v6 treatment effectively prevents radiation-induced lung fibrosis in mice, raising the possibility that such treatment might benefit patients with various forms of lung fibrosis.
Molecular characterization of the peripheral airway field of cancerization in lung adenocarcinomaTsay, Jun-Chieh J; Li, Zhiguo; Yie, Ting-An; Wu, Feng; Segal, Leopoldo; Greenberg, Alissa K; Leibert, Eric; Weiden, Michael D; Pass, Harvey; Munger, John; Statnikov, Alexander; Tchou-Wong, Kam-Meng; Rom, William N 2015; ?-?, PLoS one — id: 1473472, year: 2015, page: ?, stat: Journal Article
Sonic Hedgehog Signaling in the Lung - from Development to DiseaseKugler, Matthias C; Joyner, Alexandra L; Loomis, Cynthia A; Munger, John S 2014 Jul; 339e-341e, American journal of respiratory cell & molecular biology — id: 1089832, year: 2014, page: 339e, stat: JOURNAL ARTICLE
Hedgehog Signaling in Neonatal and Adult LungLiu, Li; Kugler, Matthias C; Loomis, Cynthia A; Samdani, Rashmi; Zhao, Zhicheng; Chen, Gregory J; Brandt, Julia P; Brownell, Isaac; Joyner, Alexandra L; Rom, William N; Munger, John S 2013 Feb; 703-710, American journal of respiratory cell & molecular biology — id: 353072, year: 2013, page: 703, stat: JOURNAL ARTICLE