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Antigen
Presentation by MHC Class II Molecules Important to Immun ity
and Autoimmunity and Extracellular Matrix Remodeling Important to Cell
Migration and Tissue Repair
Many events in cell and organ function depend on proteolytic enzymes,
enzymes which mediate irreversible cleavages in proteins and effect marked
alterations in their function, e.g. initiation of coagulation, programmed
cell death, maturation of receptors, degradation of antigens, and remodeling
of the extracellular matrix. The Chapman lab is focused on the role of
proteolytic enzymes in primarily two areas of health and disease: (1)
antigen presentation by MHC class II molecules, important to immunity
and autoimmunity; and (2) extracellular matrix remodeling important to
cell migration and tissue repair. The lab has help identify and define
the function of several endosomal cysteine proteases and the biological
roles of these enzymes continue to be the major focus of the lab. In MHC
class II antigen presentation specific and distinct cysteine enzymes cleave
antigen and mediate maturation of class II molecules for surface presentation
of antigenic peptides to T cells. One goal of the lab is to define all
of the endosomal proteases in antigen presenting cells and test the premise
that specific inhibition of one or more of these enzymes can favorably
modify the immune response to ameliorate MHC class II driven inflammatory
processes such as asthma.
Under some conditions endosomal proteases spill out into the pericellular
environment and mediate tissue degradation. This may be a normal physiological
process as occurs in bone matrix turnover or a pathogenic process as occurs
in emphysema and vascular aneurysms. Regulation of protease activity in
the extracellular space as it relates to tissue destruction is also a
major lab focus. A developing paradigm is that activation of proteolytic
enzymes couple to and regulate the function of cellular adhesion receptors,
coordinating the process of matrix attachment and detachment by cells.
Signaling through integrin adhesion receptors regulates protease activity
in the pericellular environment and proteases in turn modify the function
of integrins. A major focus in the lab is to define the physical and functional
interactions between proteases such as the plasminogen activator urokinase
and integrins and to test the proposition that this interaction is a potential
therapeutic site for interruption of inflammatory processes and/or tumor
metastasis.
Selected Publications:
Wei Y, Lukasev M, Simon DI, Bodary SC, Rosenburg S, Doyle MV, and HA Chapman.
Regulation of integrin function by the urokinase receptor Science 1996;273:1551-1555.
Gelb BD, Shi GP. Chapman HA, and RJ Desnick. Pycnodysostosis, a lysosomal
disease caused by cathepsin K deficiency. Science 1996;273:1236-1238.
Riese R, Wolf P, Bromme D, Natkin L, Villadangos JA, Ploegh H, and HA
Chapman. Essential role for cathepsin S in MHC Class II-associated invariant
chain processing and antigen presentation. Immunity 1996;4:357-366.
Shi GP, Villadangos J, Dranoff G, Ploegh H, Chapman HA. Cathepsin S required
for normal MHC class II peptide loading and germinal center development.
Immunity, 1999;10:196-206.
Wei Y, Yang X, Quimei Liu, Wilkins JA, and Chapman HA. Role for caveolin
and urokinase receptors in integrin-mediated adhesion and signaling. J
Cell Biol. 1999;144:1285-1294.
Shi G-P, Bryant R, Riese, R, Ploegh HL, Chapman HA. Role for cathepsin
F in invariant chain processing and MHC class II peptide loading by macrophages.
J Exp Med 2000; 191: 1177-1185.
Simon DI, Wei Y, Chen Z, Rao NK, Rosenberg S, Chapman HA. Identification
of a Urokinase Receptor-Integrin Interaction Site: Promiscuous Regulator
of Integrin Function. J Biol Chem 2000;275: 10228-10234.
Chapman HA. Plasminogen activators, integrins, and the coordinant regulation
of cell adhesion and migration. Current Opinion in Cell Biology 1997;9:
714-724.
Chapman, HA. Endosomal proteolysis and MHC class II function. Current
Opinion in Immunology, 1998;10:93-102.
Chapman HA and Shi GP. Protease injury in the development of COPD. Chest
2000; 117: 1-4S
Chapman HA and Wei Y. Protease crosstalk with integrins: the urokinase
receptor paradigm. Review. Thromb Haemost 2001; 86:124-129.
Wei Y, Eble JA, Wang ZM, Kreidberg JA, and Chapman HA. Urokinase receptors
promote beta1 integrin function through interactions with the integrin
alpha3beta1. Mol Biol Cell 2001; 12: 2975-2986.
Riese RJ, Shi GP, Villadangos J, Stetson D, Driessen C, Lennon-Dumenil
AM, Chu CL, Naumov Y, Behar SM, Ploegh H, Locksley R, Chapman HA. Regulation
of CD1 Function and NK1.1+ T Cell Selection and Maturation by Cathepsin
S. Immunity 2001;15, 909-919.
Contact Inforrmation:
Email: halchap@itsa.ucsf.edu
Phone: 415.514.0896 campus
Address: 505 Parnassus Ave. Box 0130
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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