4.8 Article

Perturbation of transforming growth factor (TGF)-ss1 association with latent TGF-β binding protein yields inflammation and tumors

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805411105

Keywords

TGF-beta activation

Funding

  1. National Institutes of Health [CA034282, F32 HL67542-01, T32 CA09161, AR 049698]
  2. Uehara Foundation
  3. Bausch and Lomb Overseas Research Fellowship

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Transforming growth factor-beta (TGF-beta) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-beta is often released as part of an inactive tripartite complex consisting of TGF-beta, the TGF-beta propeptide, and a molecule of latent TGF-beta binding protein (LTBP). The interaction of TGF-beta and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-beta from this state is crucial for signaling. To examine the contribution of LTBP to TGF-beta function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1(C33S/C33S) mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-beta 1 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-beta 1, decreased TGF-beta signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-beta complex is important for proper TGF-beta 1 function and that Tgfb1(C33S/C33S) mice are hypomorphs for active TGF-beta 1. Moreover, although mechanisms exist to activate latent TGF-beta 1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.

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