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Functional
Genomics of Extracellular Proteolysis
Cell-cell and cell-extracellular matrix (ECM) interactions provide cells
with information essential for controlling morphogenesis, cell-specific
fate determination, gain or loss of tissue-specific functions, cell migrations,
tissue repair and cell death. Cleavage of cell surface and ECM proteins
by matrix metalloproteinases and other proteolytic enzymes initiate rapid
and irreversible signal transduction events that lead to altered cell
behavior. The consequences of these signals are morphogenesis, cell migration,
physiologic tissue remodeling or pathologic processes.
Our laboratory uses functional genomic approaches to define the role of
proteolysis in controlling cell fate decisions, cell survival, vasculogenesis
and angiogenesis during development and tumorigenesis. Matrix metalloproteinases
play a critical role by regulating extracellular matrix and cell surface
proteins, growth and angiogenic factors, cell recruitment, cell proliferation
and apoptosis. We wish to determine the identity and function of the critical
proteinases, how their expression and activities are regulated, what the
molecular and cellular targets of the proteinases are, and how these regulate
the signaling pathways.
We are studying several critical developmental processes: endochondral
bone formation, placental morphogenesis, adipogenesis and branching morphogenesis
in the mammary gland and lung. We are also studying the mechanisms underlying
epithelial-mesenchymal communication. We are taking genetic and molecular
approaches to understand what proteinases are critical cell surface molecules,
and how they regulate EGF, VEGF, hedgehog and FGF receptor signaling.
Proteinases are universally upregulated during tumor progression. We are
using genetic approaches to understand what role they play during initiation,
progression, malignant conversion, angiogenesis and metastasis. We wish
to elucidate how proteinases regulate the cellular microenvironment and
what role they play in altering the host stroma and the recruitment and
function of inflammatory cells and endothelial cells.
Selected Publications:
Lukashev, M. E. & Z. Werb (1998). ECM signaling: orchestrating cell behavior
and misbehavior. Trends Cell Biol. 8: 437-441.
MacAuley, A., J. C. Cross & Z. Werb (1998). Reprogramming the cell cycle
for endoreduplication in rat trophoblast. Mol. Biol. Cell. 9: 795-807.
Vu, T. H., J. M. Shipley, G. Bergers, J. E. Berger, J. A. Helms, D. Hanahan,
S. D. Shapiro, R. M. Senior & Z. Werb (1998). MMP-9/gelatinase B is a
key regulator of growth plate angiogenesis and apoptosis of hypertrophic
chondrocytes. Cell. 93:411-422.
Gerber, H.-P., T. H. Vu, A.M. Ryan, J. Kowalski, Z. Werb & N. Ferrara
(1999). VEGF couples hypertrophic cartilage remodeling, ossification and
angiogenesis during endochondral bone formation. Nature Med. 5: 623-628.
Miettenin, P.J., J.R. Chin, L. Shum, H. C. Slavkin. C. F. Shuler, R. Derynck
& Z. Werb (1999). EGF receptor function is necessary for normal craniofacial
development and palate closure. Nature Gen. 22:69-73.
Sternlicht, M. D., A. Lochter, C. J. Sympson, B. Huey, J.-P. Rougier,
J. W. Gray, D. Pinkel, M. J. Bissell & Z. Werb (1999). The stromal proteinase
MMP-3/stromelysin-1 promotes mammary carcinogenesis. Cell. 98: 137-146.
Wiesen, J. F., P. Young, Z. Werb & G. R. Cunha (1999). Signaling through
the stromal epidermal growth factor receptor is necessary for mammary
ductal development. Development. 126: 335-344.
Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa,
P. Thorpe, S. Itohara, Z. Werb & D. Hanahan (2000). Gelatinase B triggers
the angiogenic switch during carcinogenesis. Nature Cell Biol 2: 737-744.
Coussens, L. M., C. L. Tinkle, D. Hanahan & Z. Werb (2000) Gelatinase
B/MMP-9 supplied by bone marrow-derived cells regulates skin carcinogenesis.
Cell. In press.
Engsig, M.T., Q.-J Chen, T. H. Vu, A.C. Pedersen, B. Therkidsen, L. Lund,
K. Henriksen, B. Winding, T. Lenhard, N. T. Foged, Z. Werb & J.-M. DelaissZÿ
(2000). MMP-9 and VEGF are essential for osteoclast recruitment into developing
long bones. J. Cell Biol. In press.
Heyer, B.S., A. MacAuley, O. Behrendtsen& Z. Werb (2000 Hypersensitivity
to DNA damage leads to increased apoptosis during early mouse development.
Genes Dev. 4: 2072-2084.
Liu, Z., X. Zhou, S. D. Shapiro, J. M. Shipley, L. A. Dias, R. M. Senior
& Z. Werb (2000). a1-proteinase inhibitor is the critical substrate for
gelatinase B/ MMP-9 in vivo. Cell. 102: 647-655.
Lund, L. R, S. F. BjÀrn, M. D. Sternlicht, B. S. Nielsen, H. Solberg,
P. A. Usner, R. østerby, I. J. Christensen, T. H. Bugge,, R. W. Stephens,
K. Dano & Z. Werb (2000). Lactational development and involution of the
mammary gland requires plasminogen. Development. 127:4481-4492.
Rinkenberger, J. & Z.Werb (2000). The labyrinthine placenta. Nature Gen.
25: 248-250. Vu, T.H. & Z. Werb (2000). Matrix metalloproteinases: effectors
of development and normal physiology. Genes Dev. 14: 2123-2134.
Contact Information:
Email: zena@itsa.ucsf.edu
Phone: 415/ 476-4622
Address: Box 0452, Room HSW 1321
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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