Perturbation of transforming growth factor (TGF)-β1 association with latent TGF-β binding protein yields inflammation and tumors

Keiji Yoshinaga, Hiroto Obata, Vladimir Jurukovski, Roberta Mazzieri, Yan Chen, Lior Zilberberg, David Huso, Jonathan Melamed, Petra Prijatelj, Vesna Todorovic, Branka Dabovic, Daniel B. Rifkin

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor-β (TGF-β) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-β is often released as part of an inactive tripartite complex consisting of TGF-β, the TGF-β propeptide, and a molecule of latent TGF-β binding protein (LTBP). The interaction of TGF-β and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-β from this state is crucial for signaling. To examine the contribution of LTBP to TGF-β function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1C33S/C33S mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-β1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1-/- animals. Tgfb1 C33S/C33S mice exhibited decreased levels of active TGF-β1, decreased TGF-β signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-β complex is important for proper TGF-β1 function and that Tgfb1 C33S/C33S mice are hypomorphs for active TGF-β1. Moreover, although mechanisms exist to activate latent TGF-β1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.

Original languageEnglish (US)
Pages (from-to)18758-18763
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number48
DOIs
StatePublished - Dec 2 2008
Externally publishedYes

Keywords

  • Tgf-β activation

ASJC Scopus subject areas

  • General

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