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Exp Cell Res. 2008 Aug 1;314(13):2488-500. doi: 10.1016/j.yexcr.2008.05.010. Epub 2008 May 29.

Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion.

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Departments of Virology and Pathology, Haartman Institute, Univertsity of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland.


Latent transforming growth factor (TGF)-beta binding proteins are extracellular matrix (ECM) proteins involved in the regulation of TGF-beta sequestration and activation. In this study, we have identified binding domains in LTBP-4, which mediate matrix targeting and cell adhesion. LTBP-4 was found to possess heparin binding activity, especially in its N-terminal region. The C-terminal domain of LTBP-4 supported fibroblast adhesion, a property reduced by soluble heparin. In addition, we found that LTBP-4 binds directly to fibronectin (FN), which was indispensable for the matrix assembly of LTBP-4. The FN binding sites were also located in the N-terminal region. Interestingly, heparin was able to reduce the binding of LTBP-4 to FN. In fibroblast cultures, LTBP-4 colocalized first with FN and subsequently with fibrillin-1, pointing to a role for FN in the early assembly of LTBP-4. In FN -/- fibroblasts, LTBP-mediated ECM targeting was disturbed, resulting in increased TGF-beta activity. These results revealed new molecular interactions which are evidently important for the ECM targeting, but which also are evidence of novel functions for LTBP-4 as an adhesion molecule.

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