Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion.
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.
Kantola
Anna K
AK
Departments of Virology and Pathology, Haartman Institute, Univertsity of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland.
Keski-Oja
Jorma
J
Koli
Katri
K
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002448:Cell Adhesion; D002450:Cell Communication; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008907:Mink; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology
D005353:Fibronectins; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D006493:Heparin