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First published online 3 May 2005
doi: 10.1242/jcs.02352

This Article Figures Only Full Text Full Text (PDF) Supplementary Material An erratum has been published All Versions of this Article: jcs.02352v1 118/10/2177    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mazzieri, R. Articles by Rifkin, D. B. Search for Related Content PubMed PubMed Citation Articles by Mazzieri, R. Articles by Rifkin, D. B.

Expression of truncated latent TGF-ß-binding protein modulates TGF-ß signaling

Roberta Mazzieri^1,*,, Vladimir Jurukovski^1,*,, Hiroto Obata^1,¶, Joanne Sung¹, Alec Platt^1,**, Eric Annes^1,, Nevena Karaman-Jurukovska², Pierre-Emmanuel Gleizes^1, and Daniel B. Rifkin^1,3,¶¶

¹ Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
² Department of Oral Biology and Pathology, State University of New York at Stony Brook, Westchester Hall, Stony Brook, NY 11794-8702, USA
³ Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

^¶¶ Author for correspondence (e-mail: rifkid01{at}med.nyu.edu)

Accepted 28 February 2005

Transforming growth factor-ß is released from most cells as an inactive complex consisting of transforming growth factor-ß, the transforming growth factor-ß propeptide and the latent transforming growth factor-ß-binding protein. We studied the role of latent transforming growth factor-ß-binding protein in modulating transforming growth factor-ß availability by generating transgenic mice that express a truncated form of latent transforming growth factor-ß-binding protein-1 that binds to transforming growth factor-ß but is missing the known N- and C-terminal matrix-binding sequences. As transforming growth factor-ß is an inhibitor of keratinocyte proliferation and is involved in the control of hair cycling, we over-expressed the mutated form of latent transforming growth factor-ß-binding protein under the control of the keratin 14-promoter. Transgenic animals displayed a hair phenotype due to a reduction in keratinocyte proliferation, an abbreviated growth phase and an early initiation of the involution (catagen) phase of the hair cycle. This phenotype appears to result from excess active transforming growth factor-ß, as enhanced numbers of pSmad2/3-positive nuclei are observed in transgenic animal skin. These data suggest that the truncated form of latent transforming growth factor-ß-binding protein-1 competes with wild-type latent transforming growth factor-ß-binding protein for binding to latent transforming growth factor-ß, resulting in latent transforming growth factor-ß complexes that fail to be targeted correctly in the extracellular matrix. The mis-localization of the transforming growth factor-ß results in inappropriate activation and premature initiation of catagen, thereby illustrating the significance of latent transforming growth factor-ß-binding protein interaction with transforming growth factor-ß in the targeting and activation of latent transforming growth factor-ß in addition to previously reported effects on small latent complex secretion.

Key words: TGF-ß, LTBP, Smad2/3, Keratinocytes, Transgenic mice, Hair cycle

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