Tenascin-C-derived Peptide TNIIIA2 Highly Enhances Cell Survival and PDGF-dependent Cell Proliferation through Potentiated and Sustained Activation of Integrin {alpha}5{beta}1 [Signal Transduction]

May 7th, 2014 by 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.

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/MAP kinase pathway in a PDGF-dependent manner. Of note, TNIIIA2 induced a 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.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Tenascin-C-derived Peptide TNIIIA2 Highly Enhances Cell Survival and PDGF-dependent Cell Proliferation through Potentiated and Sustained Activation of Integrin {alpha}5{beta}1 [Signal Transduction]