期刊
MATRIX BIOLOGY
卷 24, 期 6, 页码 418-427出版社
ELSEVIER
DOI: 10.1016/j.matbio.2005.05.005
关键词
integrin; osteopontin; thrombin; matrix metalloprotease
The extracellular matrix protein, osteopontin, is a ligand for several members of the integrin family, including alpha 5 beta 1, alpha v beta 3, alpha v beta 5 and alpha 9 beta 1. Osteopontin is a substrate for a number of extracellular proteases, including thrombin and the metalloproteases MMP-3 and MMP-7, which cleave osteopontin at sites close to or within the mapped integrin binding sites. Using affinity chromatography and cell adhesion assays, we now identify the integrin alpha v beta 6 as an additional osteopontin receptor. Utilizing a series of recombinant forms of osteopontin, we compared the structural requirements for alpha v beta 6 binding with those for the 4 other osteopontin-binding integrins. Like alpha 5 beta 1, alpha v beta 3 and alpha v beta 5 (but not alpha 9 beta 1, alpha v beta 6 binds to the RGD site in osteopontin, since RGD peptide or mutation of this site to RAA completely inhibits alpha v beta 6-mediated cell adhesion. For both alpha 9 beta 1 and alpha 5 beta 1, the N-terminal fragment generated by thrombin cleavage is a much better ligand than full length osteopontin, whereas thrombin-cleavage does not appear to be required for optimal adhesion to alpha v beta 3, alpha v beta 5 or alpha v beta 6. A recombinant fragment predicted to be generated by MMP cleavage no longer supported alpha 5 beta 1 or alpha 9 beta 1-mediated adhesion, but adhesion mediated by alpha v beta 5 or alpha v beta 6 was unaffected. Finally, adhesion of alpha v beta 5 or alpha v beta 6 was inhibited by mutation of two aspartic acid residues upstream of the RGD site, whereas adhesion mediated by alpha v beta 3, alpha 5 beta 1 or alpha 9 beta 1 was unaffected by these mutations. These results suggest that the hierarchy of integrin interactions with osteopontin can undergo complex regulation at least in part through the action of extracellular proteases. (c) 2005 Elsevier B.V./International Society of Matrix Biology. All rights reserved.
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