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J. Biol. Chem., Vol. 280, Issue 19, 18871-18880, May 13, 2005

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Fibronectin Regulates Latent Transforming Growth Factor- (TGF) by Controlling Matrix Assembly of Latent TGF-binding Protein-1^*

Sarah L. Dallas, Pitchumani Sivakumar, Carolyn J. P. Jones¶, Qian Chen, Donna M. Peters||, Deane F. Mosher||, Martin J. Humphries**, and Cay M. Kielty**

From the Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, Missouri 64108, ^¶Academic Unit of Obstetrics and Gynaecology, School of Medicine, University of Manchester, St. Mary's Hospital, Manchester M13 OJH, United Kingdom, the ^||Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706, and ^**Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Latent transforming growth factor--binding proteins (LTBPs) are extracellular matrix (ECM) glycoproteins that play a major role in the storage of latent TGF in the ECM and regulate its availability. Here we show that fibronectin is critical for the incorporation of LTBP1 and transforming growth factor- (TGF) into the ECM of osteoblasts and fibroblasts. Immunolocalization studies suggested that fibronectin provides an initial scaffold that precedes and patterns LTBP1 deposition but that LTBP1 and fibronectin are later localized in separate fibrillar networks, suggesting that the initial template is lost. Treatment of fetal rat calvarial osteoblasts with a 70-kDa N-terminal fibronectin fragment that inhibits fibronectin assembly impaired incorporation of LTBP1 and TGF into the ECM. Consistent with this, LTBP1 failed to assemble in embryonic fibroblasts that lack the gene for fibronectin. LTBP1 assembly was rescued by full-length fibronectin and superfibronectin, which are capable of assembly into fibronectin fibrils, but not by other fibronectin fragments, including a 160-kDa RGD-containing fragment that activates 51 integrins. This suggests that the critical event for LTBP1 assembly is the formation of a fibronectin fibrillar network and that integrin ligation by fibronectin molecules alone is not sufficient. Not only was fibronectin essential for the initial incorporation of LTBP1 into the ECM, but the continued presence of fibronectin was required for the continued assembly of LTBP1. These studies highlight a nonredundant role for fibronectin in LTBP1 assembly into the ECM and suggest a novel role for fibronectin in regulation of TGF via LTBP1 interactions.

Received for publication, September 20, 2004 , and in revised form, January 20, 2005.

^* This work was supported by National Institutes of Health Grants R29CA74262 and KO1CA75387 (to S. L. D.), Arthritis Research Campaign Grant D0572, and Grant RHE/0035/G from the Oliver Bird Foundation (to S. L. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: School of Dentistry, University of Missouri-Kansas City 650 E. 25th St., Kansas City, MO 64108. Tel.: 816-235-6295; Fax: 816-235-5524; E-mail: dallass{at}umkc.edu.

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