A peptide derived from tenascin-C induces beta1 integrin activation through syndecan-4.
Tenascin-C (TN-C) is unique for its cell adhesion modulatory function. We have shown that TNIIIA2, a synthetic 22-mer peptide derived from TN-C, stimulated beta1 integrin-mediated cell adhesion of nonadherent and adherent cell types, by inducing activation of beta1 integrin. The active site of TNIIIA2 appeared cryptic in the TN-C molecule but was exposed by MMP-2 processing of TN-C. The following results suggest that cell surface heparan sulfate (HS) proteoglycan (HSPG), including syndecan-4, participated in TNIIIA2-induced beta1 integrin activation: 1) TNIIIA2 bound to cell surface HSPG via its HS chains, as examined by photoaffinity labeling; 2) heparitinase I treatment of cells abrogated beta1 integrin activation induced by TNIIIA2; 3) syndecan-4 was isolated by affinity chromatography using TNIIIA2-immobilized beads; 4) small interfering RNA-based down-regulation of syndecan-4 expression reduced TNIIIA2-induced beta1 integrin activation, and consequent cell adhesion to fibronectin; 5) overexpression of syndecan-4 core protein enhanced TNIIIA2-induced activation of beta1 integrin. However, treatments that targeted the cytoplasmic region of syndecan-4, including ectopic expression of its mutant truncated with the cytoplasmic domains and treatment with protein kinase Calpha inhibitor Gö6976, did not influence the TNIIIA2 activity. These results suggest that a TNIIIA2-related matricryptic site of the TN-C molecule, exposed by MMP-2 processing, may have bound to syndecan-4 via its HS chains and then induced conformational change in beta1 integrin necessary for its functional activation. A lateral interaction of beta1 integrin with the extracellular region of the syndecan-4 molecule may be involved in this conformation change.
Saito
Yohei
Y
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
Imazeki
Hisae
H
Miura
Shogo
S
Yoshimura
Tomohisa
T
Okutsu
Hiroaki
H
Harada
Yosei
Y
Ohwaki
Toshiyuki
T
Nagao
Osamu
O
Kamiya
Sadahiro
S
Hayashi
Ryo
R
Kodama
Hiroaki
H
Handa
Hiroshi
H
Yoshida
Toshimichi
T
Fukai
Fumio
F
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019012:Integrin beta1 / Q000378:metabolism*; D020014:K562 Cells; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D053671:Syndecan-4 / Q000378:metabolism*; D019063:Tenascin / Q000737:chemistry*
D002227:Carbazoles; D006497:Heparan Sulfate; D007211:Indoles; D019012:Integrin beta1; D010455:Peptides; D053671:Syndecan-4; D019063:Tenascin; C081021:Go 6976