Dean Sheppard, M.D.
Professor of Medicine

Contact Information:
dean.sheppard@ucsf.edu
Tel: 514-4269
Fax: 514-4278
1550 4th Street
Rock Hall, Room 548E
Box 2922

Links:
Lab website
Cell Biology/PIBS
Biomedical Sciences
Pulmonary and Critical Care Medicine

Publications
Link to PubMed
Recent Publications

In vivo functions of integrins/ molecular pathways underlying common lung diseases

My lab focuses on how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues. Much of the work is focused on two members of this family, the epithelial-restricted integrin, and the widely expressed integrin a9ß1. avß6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFß), that depend on distinct sequences in the ß6 cytoplasmic domain. Currently we are identifying pathways that regulate each of these responses and are using tissue specific rescue transgenes in ß6 ko mice to characterize the roles of these pathways in vivo.

a9ß1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. a9ß1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As a9 ko mice are not viable, we are generating mice expressing a conditional null allele to better the role of this integrin in vivo.

Current treatments of most common lung diseases are ineffective or toxic, in part due to limited understanding of the molecular events underlying these diseases. We are taking an unbiased approach to this problem, combining global analysis of gene expression and computational analysis of genetic loci responsible for differences in disease models in inbred strains of mice. In parallel, we are generating mice expressing null mutations of leading candidate genes identified from our screening approaches.

Recent Publications:
Munger JS, Huang XZ , Kawakatsu H , Griffiths MJD, Dalton SL, Wu JF, Pittet JF, Kaminiski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin avß6 binds and activates latent TGFß1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999, 96: 319-328.

Taaoka, Y., J. Chen, T. Yednock and D. Sheppard. The integrin a9ß1 mediates adhesion to activated endothelial cells and trans-endothelial neutrophil migration through interaction with vascular cell adhesion molecule 1. J Cell Biol 1999, 145:413-420.

Kaminiski N, Allard J, Pittet J-F, Zuo F, Griffiths MJD, Morris D, Huang XZ, Sheppard D, Heller RA. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and remodeling. Proc Nat Acad Sci 2000 97:1778-1783.

Pittet J-F, Griffiths MJD, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LAS, Gotwals PJ, Koetiansky VE, Matthay MA, Sheppard D. TGFß is a critical mediator of acute lung injury. J. Clin. Invest. 2001 107:1529-1536.

Young BA, Taooka Y, Liu S, Askins J, Yokosaki Y, Thomas SM, Sheppard D. The cytoplasmic domain of the integrin a9 subunit requires the adaptor protein paxillin to inhibit cell spreading but promotes cell migration in a paxillin-independent manner. Mol Biol Cell 2001 12:3214-3225.

Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A, Sheppard D. Loss of integrin avß6-mediated TGFß activation causes Mmp12-dependent emphysema. Nature 2003 422:169-173.