Dean Sheppard, MD

Dean Sheppard, MD

Professor, Department of Medicine, UCSF

Phone: (415) 514-4269 (voice)
Box 2922, UCSF
San Francisco, CA 94143-2922

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Cancer Center Membership

Associate Member » Non-aligned

Research Summary

Dean Sheppard received an AB (Social Studies) from Harvard College in 1972, and an MD from SUNY at Stony Brook in 1975. He trained in Internal Medicine at the University of Washington in Seattle and in Pulmonary Medicine at UCSF. He has been on the faculty of UCSF since 1980 and was appointed the founding director of the Lung Biology Research Center in 1986. He has been the Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep since 2009. Dr. Sheppard is Professor of Medicine and a member of the Cell Biology, Biomedical Sciences, Immunology and Pharmaceutical Sciences and Pharmacogenomics graduate programs.

Research Interests

Dr. Sheppard’s research focuses on the molecular mechanisms underlying pulmonary (and other organ) fibrosis, asthma and acute lung injury. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common lung diseases. Utilizing mice with global or conditional knockouts of four integrins, the epithelial-restricted integrin, avß6, and the widely expressed integrins a9ß1, avß1, avß5 and avß8, the lab has identified important roles for these integrins in models of each common lung disease and key steps upstream and downstream of the integrins that provide potential therapeutic targets.

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. We have shown that the latter function plays a central role in pulmonary and renal fibrosis, acute lung injury, protection from pulmonary emphysema, tumor invasion and in the airway hyperresponsiveness that follows chronic allergen challenge. Currently we are identifying pathways that regulate each of these responses. A humanized monoclonal antibody generated by immunizing our knockout mice is currently in clinical trials for treatment of pulmonary and renal fibrosis. We have also found that mice lacking all av integrins on myofibroblasts are protected from pulmonary, hepatic and renal fibrosis and are using this model to develop new approaches for treating a wide variety of fibrotic diseases.

The avß8 integrin also activates TGFß. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting avß8-mediated TGFß activation on dendritic cells negatively regulates adaptive immunity. However, these mice are dramatically protected from pathology in a number of immune-mediated disease models, including a model of allergic asthma. We are currently characterizing the mechanisms underlying these effects, the mechanisms by which this process is regulated during the induction of adaptive immune responses, and the relevance of this pathway in various models of immune-mediated disease.

The avß1 integrin is an understudied integrin that is expressed on fibroblasts and smooth muscle cells. Together with Bill DeGrado, we have generated a potent and specific small molecule inhibitor of this integrin and shown that also activates TGFß and plays a critical role in driving tissue fibrosis in several organs, including the lung, kidney and liver. We are currently working to develop even better small molecule inhibitors and reagents that will allow us to more accurately follow expression of this integrin 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. As a9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. Mice lacking this integrin in airway smooth muscle cells develop spontaneous airway hyperresponsiveness, resembling asthma. We have used these mice and cells and tissues from their lungs to identify a completely novel pathway regulating airway smooth muscle contraction, and are currently working to develop specific inhibitors of pathway components in the hope of finding new treatments for asthma.

avß5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice are dramatically protected in multiple models of acute lung injury and septic shock. This phenotype is explained, at least in part, by a central role for this integrin in regulating reorganization of the actin cytoskeleton in activated endothelial cells. We are currently examining the mechanisms by which this integrin, and its close relative, avß3, exert opposing effects on actin organization, vascular permeability and tissue edema. We have also generated a potent blocking antibody to avß5 that we hope to develop for treatment of acute lung injury and septic shock.


Harvard College, Cambridge, MA, A.B., 1972
SUNY at Stony Brook, Stony Brook, NY, M.D., 1975, Medicine
Univ of Washington, Seattle, WA, Resident, 1975-78, Internal Medicine
Univ of California, San Francisco, San Francisco, Fellow, 1978-80, Pulmonary

Professional Experience

  • 1986-present
    Director, Lung Biology Center, University of California, San Francisco
  • 1981-87
    Assistant Professor of Medicine, University of California, San Francisco
  • 1987-92
    Associate Professor of Medicine, University of California, San Francisco
  • 1992-present
    Professor of Medicine, University of California, San Francisco
  • 1997-present
    Associate Chair for Biomedical Research, Department of Medicine, UCSF
  • 2000-present
    Member, NHLBI Program Project Review Committee. 1998-2002, Chair 2000-2002
  • 2004-present
    Member, Lung Injury and Repair Study Section

Honors & Awards

  • Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282:226-228.
  • 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 avb6 binds and activates latent TGFb1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96:319-328.
  • Taaoka Y, J Chen, T Yednock and D Sheppard. The integrin a9b1 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.
  • Kaminski 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.
  • Huang XZ, Griffiths M, Wu JF, Farese RV, Sheppard D. Impaired cell migration and adhesion but normal development in b5 deficient mice. Mol Cell Biol 2000; 20:755-759.
  • Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV Jr, Sheppard D. Fatal bilateral chylothorax in mice lacking the integrin a9b1. Mol Cell Biol 2000; 20:5208-5215.
  • Marcinkiewicz C, Taooka Y, Yokosaki Y, Calvete JJ, Marcinkiewicz MM, Lobb RR, Niewiarowski S, Sheppard D. Inhibitory effects of MLDG-containing heterodimeric disintegrins reveal distinct structural requirements for interaction of the integrin a9b1 with VCAM-1, tenascin-C and osteopontin. J Biol Chem 2000; 275:31930-31937.
  • Miller LC, Blakemore W, Sheppard D, Atakilit AA, King AMQ, Jackson T. Role of the cytoplasmic domain of the b subunit of the integrin avb6 in infection by foot and mouth disease virus. J Virology 2001, 75:4158-4164.
  • Pittet J-F, Griffiths MJD, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LAS, Gotwals PJ, Koetiansky VE, Matthay MA, Sheppard D. TGFb 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.
  • Reynolds LE, Wyder L, Lively JG, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM. Enhanced angiogenesis in b3 integrin-deficient and b3/b5 integrin-deficient mice. Nature Medicine 2002; 8:27-34.
  • Jackson T, Mould PA, Sheppard D, King AMQ. The integrin avb1 is a receptor for foot-and-mouth disease virus. J Virology 2002; 76:935-941.
  • Elicieri BP, Puente XS, Hood JD, Huang X, Schlaepfer DA, Sheppard D, Cheresh DA. VEGF endothelial response requires src-mediated coupling of FAK to integrin avb5 J. Cell Biol. 2002 157:149-160.
  • Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger J, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL. The integrin avb8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-b1. J Cell Biol 2002 157:493-507.
  • Zuo F, Kaminski N, Fugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller R. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Nat Acad Sci (USA) 2002; 99:6292-6297.
  • Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van de Water L, The EIIIA segment of fibronectin is a ligand for the integrins a9b1 and a4b1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 2002; 277:14467-14474.
  • Eto K, Huet C, Tarui T, Kupriyanov S, Liu H-Z, Puzon-McLaughlin W, Zhang X-P, Sheppard D, Engvall E, Takada Y. Functional classification of ADAMs based on a conserved motif for binding to integrin a9b1; implications for sperm-egg binding and other cell interactions. J. Biol. Chem 2002 277:17804-10.
  • Knight PA, Wright SH, Brown JK, Huang X, Sheppard D, Miller HRP. Enteric expression of the integrin avb6 is essential for nematode-induced mucosal mast cell hyperplasia and expression of the granule chymase, mouse mast cell protease-1. Am J Pathol 2002 161:771-779.
  • Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A, Sheppard D. Loss of integrin avb6-mediated TGFb activation causes Mmp12-dependent emphysema. Nature 2003 422:169-173.
  • Frank J, Roux J, Kawakatsu H, Su G, Dagenais A, Berthiaume Y, Howard MB, Canessa C, Fang XH, Sheppard D, Matthay MA, Pittet JF. TGF-b1 decreases _ENaC expression and alveolar epithelial vectorial sodium and fluid transport via an ERK 1/2-dependent mechanism. J Biol Chem 2003 278:43939-43950.
  • Ma L-J, Yang H, Gaspert H, Carlesso G, Davidson JM, Sheppard D, Fogo AM, Transforming growth factor-b dependent and independent pathways of induction of tubulointerstitial fibrosis in b6-/- mice Am J Pathol 2003 163:1261-73.
  • Lind DL, Choudhry S, Ung N, Ziv E, Avila PC, Coyle NE, Salari K, Nazario S, Casal J, Torres A, Rodriguez-Santana AJ, Matallana H, Lilly CM, Salas J, Selman M, Boushey HA, Weiss ST, Chapela R, Ford JG, Rodriguez-Cintron W, Silverman EK, Sheppard D, Kwok P-Y and Burchard EG. ADAM33 is not associated with asthma in Latino populations. Am J Respir Crit Care Med 2003 168:1312-1316.
  • Bazan-Socha S, Kisiel DG, Young B, Theakston DG, Calvete JJ, Sheppard D, Marcinkiewicz C. Structural requirements of MLD-containing disintegrins for functional interactions with a4b1 and a9b1 integrins. Biochemistry 2004 43:1639-1647.
  • Weinreb PH, Simon KJ, Rayborn P, Yang WJ, Leone DR, Dolinski BM, Yokota Y, Kawakatsu H, Atakilit A, Sheppard D, Violette SM. Function-blocking integrin avb6 antibodies: Distinct ligand mimetic and non-ligand-mimetic classes. J Biol Chem 2004 279:17875-87.
  • Chen C, Young BA, Coleman CS, Pegg AE, Sheppard D. Spermidine/Spermine N1-Acetyltransferase specifically binds to the integrin a9 subunit cytoplasmic domain and enhances cell migration J Cell Biol 2004 (in press).

Selected Publications

  1. Plaks V, Boldajipour B, Linnemann JR, Nguyen NH, Kersten K, Wolf Y, Casbon AJ, Kong N, van den Bijgaart RJ, Sheppard D, Melton AC, Krummel MF, Werb Z. Adaptive Immune Regulation of Mammary Postnatal Organogenesis. Dev Cell. 2015 Sep 14; 34(5):493-504.
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  2. Li JT, Melton AC, Su G, Hamm DE, LaFemina M, Howard J, Fang X, Bhat S, Huynh KM, O'Kane CM, Ingram RJ, Muir RR, McAuley DF, Matthay MA, Sheppard D. Unexpected Role for Adaptive aßTh17 Cells in Acute Respiratory Distress Syndrome. J Immunol. 2015 Jul 1; 195(1):87-95.
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  3. Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, Sheppard D. The avß1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med. 2015 May 20; 7(288):288ra79.
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  4. Sheppard D. Epithelial-Mesenchymal Interactions in Fibrosis and Repair. Transforming Growth Factor-ß Activation by Epithelial Cells and Fibroblasts. Ann Am Thorac Soc. 2015 Mar; 12 Suppl 1:S21-3.
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  5. Xu P, Bailey-Bucktrout S, Xi Y, Xu D, Du D, Zhang Q, Xiang W, Liu J, Melton A, Sheppard D, Chapman HA, Bluestone JA, Derynck R. Innate Antiviral Host Defense Attenuates TGF-ß Function through IRF3-Mediated Suppression of Smad Signaling. Mol Cell. 2014 Dec 18; 56(6):723-37.
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  6. Arnold TD, Niaudet C, Pang MF, Siegenthaler J, Gaengel K, Jung B, Ferrero GM, Mukouyama YS, Fuxe J, Akhurst R, Betsholtz C, Sheppard D, Reichardt LF. Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking aVß8-TGFß signaling in the brain. Development. 2014 Dec; 141(23):4489-99.
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  7. Bhattacharya M, Sundaram A, Kudo M, Farmer J, Ganesan P, Khalifeh-Soltani A, Arjomandi M, Atabai K, Huang X, Sheppard D. IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction. J Clin Invest. 2014 Nov 3; 124(11):4895-8.
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  8. Erle DJ, Sheppard D. The cell biology of asthma. J Cell Biol. 2014 Jun 9; 205(5):621-31.
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  9. Ito K, Morimoto J, Kihara A, Matsui Y, Kurotaki D, Kanayama M, Simmons S, Ishii M, Sheppard D, Takaoka A, Uede T. Integrin a9 on lymphatic endothelial cells regulates lymphocyte egress. Proc Natl Acad Sci U S A. 2014 Feb 25; 111(8):3080-5.
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  10. Madala SK, Korfhagen TR, Schmidt S, Davidson C, Edukulla R, Ikegami M, Violette SM, Weinreb PH, Sheppard D, Hardie WD. Inhibition of the avß6 integrin leads to limited alteration of TGF-a-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2014 Apr 15; 306(8):L726-35.
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  11. Blackwell TS, Tager AM, Borok Z, Moore BB, Schwartz DA, Anstrom KJ, Bar-Joseph Z, Bitterman P, Blackburn MR, Bradford W, Brown KK, Chapman HA, Collard HR, Cosgrove GP, Deterding R, Doyle R, Flaherty KR, Garcia CK, Hagood JS, Henke CA, Herzog E, Hogaboam CM, Horowitz JC, King TE, Loyd JE, Lawson WE, Marsh CB, Noble PW, Noth I, Sheppard D, Olsson J, Ortiz LA, O'Riordan TG, Oury TD, Raghu G, Roman J, Sime PJ, Sisson TH, Tschumperlin D, Violette SM, Weaver TE, Wells RG, White ES, Kaminski N, Martinez FJ, Wynn TA, Thannickal VJ, Eu JP. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med. 2014 Jan 15; 189(2):214-22.
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  12. Travis MA, Sheppard D. TGF-ß activation and function in immunity. Annu Rev Immunol. 2014; 32:51-82.
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  13. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D. Targeting of av integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013 Dec; 19(12):1617-24.
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  14. Goh YP, Henderson NC, Heredia JE, Red Eagle A, Odegaard JI, Lehwald N, Nguyen KD, Sheppard D, Mukundan L, Locksley RM, Chawla A. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc Natl Acad Sci U S A. 2013 Jun 11; 110(24):9914-9.
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  15. Katsumoto TR, Kudo M, Chen C, Sundaram A, Callahan EC, Zhu JW, Lin J, Rosen CE, Manz BN, Lee JW, Matthay MA, Huang X, Sheppard D, Weiss A. The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases. J Clin Invest. 2013 May 1; 123(5):2037-48.
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  16. Sheppard D. ROCKing pulmonary fibrosis. J Clin Invest. 2013 Mar 1; 123(3):1005-6.
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  17. Su G, Atakilit A, Li JT, Wu N, Luong J, Chen R, Bhattacharya M, Sheppard D. Effective treatment of mouse sepsis with an inhibitory antibody targeting integrin avß5. Crit Care Med. 2013 Feb; 41(2):546-53.
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  18. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med. 2013 Jan 9; 5(167):167sr1.
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  19. Freimuth J, Clermont FF, Huang X, DeSapio A, Tokuyasu TA, Sheppard D, Akhurst RJ. Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc Natl Acad Sci U S A. 2012 Oct 30; 109(44):18042-7.
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  20. Henderson NC, Sheppard D. Integrin-mediated regulation of TGFß in fibrosis. Biochim Biophys Acta. 2013 Jul; 1832(7):891-6.
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