Abstract
In addition to its recognition by alpha3beta1 and alpha4beta1 integrins, the N-terminal pentraxin module of thrombospondin-1 is a ligand for alpha6beta1 integrin. alpha6beta1 integrin mediates adhesion of human microvascular endothelial and HT-1080 fibrosarcoma cells to immobilized thrombospondin-1 and recombinant N-terminal regions of thrombospondin-1 and thrombospondin-2. alpha6beta1 also mediates chemotaxis of microvascular cells to thrombospondin-1 and thrombospondin-2. Using synthetic peptides, LALERKDHSG was identified as an alpha6beta1-binding sequence in thrombospondin-1. This peptide inhibited alpha6beta1-dependent cell adhesion to thrombospondin-1, thrombospondin-2, and the E8 fragment of murine laminin-1. The Glu residue in this peptide was required for activity, and the corresponding residue (Glu90) in the N-terminal module of thrombospondin-1 was required for its recognition by alpha6beta1, but not by alpha4beta1. alpha6beta1 was also expressed in human umbilical vein endothelial cells; but in these cells, only certain agonists could activate the integrin to recognize thrombospondins. Selective activation of alpha6beta1 integrin in microvascular endothelial cells by the anti-beta1 antibody TS2/16 therefore accounts for their adhesion responses to thrombospondins and explains the distinct functions of alpha4beta1 and alpha6beta1 integrins as thrombospondin receptors in microvascular and large vessel endothelial cells.
Highlights
In addition to its recognition by ␣31 and ␣41 integrins, the N-terminal pentraxin module of thrombospondin-1 is a ligand for ␣61 integrin. ␣61 integrin mediates adhesion of human microvascular endothelial and HT-1080 fibrosarcoma cells to immobilized thrombospondin-1 and recombinant N-terminal regions of thrombospondin-1 and thrombospondin-2. ␣61 mediates chemotaxis of microvascular cells to thrombospondin-1 and thrombospondin-2
The Glu residue in this peptide was required for activity, and the corresponding residue (Glu90) in the N-terminal module of thrombospondin-1 was required for its recognition by ␣61, but not by ␣41. ␣61 was expressed in human umbilical vein endothelial cells; but in these cells, only certain agonists could activate the integrin to recognize thrombospondins
Because 1-dependent interactions of TSP1 or TSP2 with endothelial cells could not be completely inhibited by ␣31 antagonists, we examined the role of additional 1 integrins expressed on endothelial cells as TSP receptors
Summary
Vol 278, No 42, Issue of October 17, pp. 40679 –40687, 2003 Printed in U.S.A. Recognition of the N-terminal Modules of Thrombospondin-1 and Thrombospondin-2 by ␣61 Integrin*. Cells can modulate their interactions with the extracellular matrix through regulating the expression or ligand-binding activities of specific integrins [1]. We previous reported that ␣31 mediates a pro-angiogenic activity of the N-terminal pentraxin module of TSP1 [18]. This integrin is constitutively expressed on venous and microvascular endothelial cells, but its ability to bind TSP1 is regulated by cell-cell signaling involving VE-cadherin [18]. Because 1-dependent interactions of TSP1 or TSP2 with endothelial cells could not be completely inhibited by ␣31 antagonists, we examined the role of additional 1 integrins expressed on endothelial cells as TSP receptors.. We identify a specific sequence in the N-terminal module of TSP1 that mediates this interaction and demonstrate that this sequence antagonizes interactions of ␣61 with its well characterized ligand laminin-1
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