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J. Cell Biol. 175 (1): 111-120

Copyright © 2006 by the Rockefeller University Press.


Article

BMP1 controls TGFß1 activation via cleavage of latent TGFß-binding protein

Gaoxiang Ge1, and Daniel S. Greenspan1,2

1 Department of Pathology and Laboratory Medicine and 2 Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706

Correspondence to Daniel S. Greenspan: dsgreens{at}wisc.edu

Abstract: Transforming growth factor ß1 (TGFß1), an important regulator of cell behavior, is secreted as a large latent complex (LLC) in which it is bound to its cleaved prodomain (latency-associated peptide [LAP]) and, via LAP, to latent TGFß-binding proteins (LTBPs). The latter target LLCs to the extracellular matrix (ECM). Bone morphogenetic protein 1 (BMP1)–like metalloproteinases play key roles in ECM formation, by converting precursors into mature functional proteins, and in morphogenetic patterning, by cleaving the antagonist Chordin to activate BMP2/4. We provide in vitro and in vivo evidence that BMP1 cleaves LTBP1 at two specific sites, thus liberating LLC from ECM and resulting in consequent activation of TGFß1 via cleavage of LAP by non–BMP1-like proteinases. In mouse embryo fibroblasts, LAP cleavage is shown to be predominantly matrix metalloproteinase 2 dependent. TGFß1 is a potent inducer of ECM formation and of BMP1 expression. Thus, a role for BMP1-like proteinases in TGFß1 activation completes a novel fast-forward loop in vertebrate tissue remodeling.

Abbreviations used in this paper: AEBSF, 4-(2-aminoethyl)-benzenesulfonyl fluoride; BMP, bone morphogenetic protein; dpc, days post conception; GDF, growth and differentiation factor; LAP, latency-associated peptide; LLC, large latent complex; LTBP, latent TGFß-binding protein; MEF, mouse embryo fibroblast; MMP, matrix metalloproteinase; SLC, small latent complex; TAPI-2, TNF-{alpha} processing inhibitor 2; TIMP, tissue inhibitor of metalloproteinase; T-MLEC, transfected mink lung epithelial cell.


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