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. (c) 2008 Elsevier Inc. All rights reserved.
机构:Univ Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, England
Bax, Daniel V.
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Mahalingam, Yashithra
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Mahalingam, Yashithra
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Cain, Stuart
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Mellody, Kieran
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Freeman, Lyle
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Freeman, Lyle
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Younger, Kerri
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Younger, Kerri
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Shuttleworth, C. Adrian
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Shuttleworth, C. Adrian
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Humphries, Martin J.
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Humphries, Martin J.
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Couchman, John R.
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Couchman, John R.
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Kielty, Cay M.
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Univ Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, EnglandUniv Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, England
机构:Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
Chaudhry, Shazia S.
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Cain, Stuart A.
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Cain, Stuart A.
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Morgan, Amanda
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Morgan, Amanda
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Dallas, Sarah L.
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Dallas, Sarah L.
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Shuttleworth, C. Adrian
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Shuttleworth, C. Adrian
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Kielty, Cay M.
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Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, EnglandUniv Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
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Univ Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, AustraliaUniv Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, Australia
Hirani, Rena
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Hanssen, Eric
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Gibson, Mark A.
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机构:Univ Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, England
Bax, Daniel V.
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Mahalingam, Yashithra
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Mahalingam, Yashithra
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Cain, Stuart
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Mellody, Kieran
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Freeman, Lyle
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Freeman, Lyle
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Younger, Kerri
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Younger, Kerri
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Shuttleworth, C. Adrian
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Shuttleworth, C. Adrian
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Humphries, Martin J.
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Humphries, Martin J.
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Couchman, John R.
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机构:Univ Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, England
Couchman, John R.
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Kielty, Cay M.
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Univ Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, EnglandUniv Manchester, Fac Life Sci, UK Ctr Tissue Engn, Manchester M13 9PT, Lancs, England
机构:Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
Chaudhry, Shazia S.
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Cain, Stuart A.
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Cain, Stuart A.
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Morgan, Amanda
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Morgan, Amanda
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Dallas, Sarah L.
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Dallas, Sarah L.
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Shuttleworth, C. Adrian
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Shuttleworth, C. Adrian
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Kielty, Cay M.
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Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, EnglandUniv Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
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Univ Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, AustraliaUniv Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, Australia
Hirani, Rena
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Hanssen, Eric
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Gibson, Mark A.
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Univ Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, AustraliaUniv Adelaide, Sch Med Sci, Discipline Pathol, Adelaide, SA 5005, Australia