Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors.
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-beta1 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-beta1, 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-beta1 function and that Tgfb1(C33S/C33S) mice are hypomorphs for active TGF-beta1. Moreover, although mechanisms exist to activate latent TGF-beta1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.
Yoshinaga
Keiji
K
Department of Cell Biology, New York University Langone School of Medicine, New York, NY 10016, USA.
Obata
Hiroto
H
Jurukovski
Vladimir
V
Mazzieri
Roberta
R
Chen
Yan
Y
Zilberberg
Lior
L
Huso
David
D
Melamed
Jonathan
J
Prijatelj
Petra
P
Todorovic
Vesna
V
Dabovic
Branka
B
Rifkin
Daniel B
DB
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007801:Langerhans Cells / Q000166:cytology / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D053779:Latent TGF-beta Binding Proteins; D011498:Protein Precursors; D053773:Transforming Growth Factor beta1