title: Tenascin-C-derived peptide TNIIIA2 highly enhances cell survival and platelet-derived growth factor (PDGF)-dependent cell proliferation through potentiated and sustained activation of integrin α5β1.
abstract: Tenascin-C is an adhesion modulatory matrix protein that is highly expressed in tumors; however, its biochemical activity involved in tumorigenesis is not fully understood. On the other hand, increasing evidence indicates the importance of integrin α5β1 in cancer development. We previously demonstrated that tenascin-C harbors a functional site that can be released as a proadhesive peptide such as TNIIIA2. Peptide TNIIIA2 is capable of inducing activation of β1-integrins including α5β1 via syndecan-4. In this study the proadhesive effect of TNIIIA2 was characterized by potentiated and sustained activation of integrin α5β1. Based on this effect, TNIIIA2 rendered nontransformed fibroblasts (NIH3T3) resistant to serum deprivation-elicited anoikis through activation of the Akt/Bcl-2 pathway. Moreover, TNIIIA2 hyperstimulated PDGF-dependent proliferation of NIH3T3 by activating integrin α5β1. Tenascin-C, a parental protein of TNIIIA2, also stimulated PDGF-dependent proliferation, which was blocked by a matrix metalloproteinase-2/9 inhibitor and an anti-TNIIIA2 function-blocking antibody, suggesting proteolytic exposure of the proadhesive effect of TNIIIA2. Mechanistic analyses revealed that TNIIIA2 induced a lateral association of PDGF receptor β with the molecular complex of activated integrin α5β1 and syndecan-4 in the membrane microdomains enriched with cholesterol/caveolin-1, resulting in prolonged activation of PDGF receptor β and the subsequent Ras/mitogen-activated protein kinase pathway in a PDGF-dependent manner. Of note, TNIIIA2 induced continuous proliferation in NIH3T3 in an integrin α5β1-dependent manner even after they formed a confluent monolayer. Thus, it was proposed that tenascin-C might be involved in deregulated cell growth through potentiated and sustained activation of integrin α5β1 after exposure of the proadhesive effect of TNIIIA2.
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seki
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Drug Informatics, Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane-shi, Chiba 283-8555, Japan.
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Kamiya
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Motomichi
authors.initials: M
authors.lastname: Fujita
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okutsu
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iyoda
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takai
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Owaki
authors.affiliation: Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Tokyo 162-8601, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yajima
authors.affiliation: Department of Chemistry, Kurume University School of Medicine, Kurume 830-0011, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Taira
authors.affiliation: Faculty of Science and Engineering, Saga University, Saga 849-0922, Japan, and.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Faculty of Science and Engineering, Saga University, Saga 849-0922, Japan, and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kodama
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan, fukai@rs.noda.tus.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Fukai
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010455:Peptides; D010982:Platelet-Derived Growth Factor; D019030:Receptors, Vitronectin; C508304:SDC4 protein, human; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D019063:Tenascin; C094340:integrin alphavbeta1; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Cell Adhesion; Cell Proliferation; Extracellular Matrix; Integrin; PDGF; Tenascin