RRC ID |
45065
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著者 |
Tanaka R, Seki Y, Saito Y, Kamiya S, Fujita M, Okutsu H, Iyoda T, Takai T, Owaki T, Yajima H, Taira J, Hayashi R, Kodama H, Matsunaga T, Fukai F.
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タイトル |
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.
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ジャーナル |
J Biol Chem
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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.
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巻・号 |
289(25)
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ページ |
17699-708
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公開日 |
2014-6-20
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DOI |
10.1074/jbc.M113.546622
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PII |
S0021-9258(20)40610-6
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PMID |
24808173
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PMC |
PMC4067204
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MeSH |
Animals
Cell Proliferation / drug effects*
Cell Survival / drug effects
Humans
K562 Cells
Membrane Microdomains / genetics
Membrane Microdomains / metabolism
Mice
NIH 3T3 Cells
Peptides / chemistry
Peptides / pharmacology*
Platelet-Derived Growth Factor / genetics
Platelet-Derived Growth Factor / metabolism*
Receptor, Platelet-Derived Growth Factor beta / genetics
Receptor, Platelet-Derived Growth Factor beta / metabolism
Receptors, Vitronectin / genetics
Receptors, Vitronectin / metabolism*
Syndecan-4 / genetics
Syndecan-4 / metabolism
Tenascin / chemistry
Tenascin / pharmacology*
|
IF |
4.238
|
引用数 |
20
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
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リソース情報 |
ヒト・動物細胞 |
K562 |