Recognition of the N-terminal Modules of Thrombospondin-1 and Thrombospondin-2 by α6β1 Integrin

In addition to its recognition by α 3 β 1 and α 4 β 1 integrins, the N-terminal pentraxin module of thrombospondin-1 is a ligand for α 6 β 1 integrin. α 6 β 1 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. α 6 β 1 also mediates chemotaxis of microvascular cells to thrombospondin-1 and thrombospondin-2. Using synthetic peptides, LALERKDHSG was identified as an α 6 β 1 -binding sequence in thrombospondin-1. This peptide inhibited α 6 β 1 -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 (Glu 90 ) in the N-terminal module of thrombospondin-1 was required for its recognition by α 6 β 1 , but not by α 4 β 1 . α 6 β 1 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 α 6 β 1 integrin in microvascular endothelial cells by the anti-β 1 antibody TS2/16 therefore accounts for their adhesion responses to thrombospondins and explains the distinct functions of α 4 β 1 and α 6 β 1 integrins as thrombospondin receptors in microvascular and large vessel endothelial cells.