Recognition of the N-terminal modules of thrombospondin-1 and thrombospondin-2 by alpha6beta1 integrin.
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.
Calzada
Maria J
MJ
Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892-1500, USA.
Sipes
John M
JM
Krutzsch
Henry C
HC
Yurchenco
Peter D
PD
Annis
Douglas S
DS
Mosher
Deane F
DF
Roberts
David D
DD
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D008833:Microcirculation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000378:metabolism; D019699:Thrombospondins / Q000737:chemistry* / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D000099262:Thrombospondin 2
D039121:Integrin alpha6beta1; D007797:Laminin; D008024:Ligands; D010455:Peptides; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C121346:laminin 1