The Novel α4B Murine α4 Integrin Protein Splicing Variant Inhibits α4 Protein-dependent Cell Adhesion

• Published in: The Journal of biological chemistry 2014-06, Vol.289 (23), p.16389-16398
• Main Authors: Kouro, Hitomi, Kon, Shigeyuki, Matsumoto, Naoki, Miyashita, Tomoe, Kakuchi, Ayaka, Ashitomi, Dai, Saitoh, Kodai, Nakatsuru, Takuya, Togi, Sumihito, Muromoto, Ryuta, Matsuda, Tadashi
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Cell Adhesion; Cytoplasm - metabolism; DNA Primers; Extracellular Matrix; Fibronectins - metabolism; Glycobiology and Extracellular Matrices; Integrin alpha4 - chemistry; Integrin alpha4 - genetics; Integrin alpha4 - metabolism; Integrins; Mice; NIH 3T3 Cells; Osteopontin - metabolism; Protein Splicing; RNA, Messenger - genetics; Tumor Metastases; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.553610

Integrins affect the motility of multiple cell types to control cell survival, growth, or differentiation, which are mediated by cell-cell and cell-extracellular matrix interactions. We reported previously that the α9 integrin splicing variant, SFα9, promotes WT α9 integrin-dependent adhesion. In this study, we introduced a new murine α4 integrin splicing variant, α4B, which has a novel short cytoplasmic tail. In inflamed tissues, the expression of α4B, as well as WT α4 integrin, was up-regulated. Cells expressing α4B specifically bound to VCAM-1 but not other α4 integrin ligands, such as fibronectin CS1 or osteopontin. The binding of cells expressing WT α4 integrin to α4 integrin ligands is inhibited by coexpression of α4B. Knockdown of α4B in metastatic melanoma cell lines results in a significant increase in lung metastasis. Expression levels of WT α4 integrin are unaltered by α4B, with α4B acting as a regulatory subunit for WT α4 integrin by a dominant-negative effect or inhibiting α4 integrin activation. α4 Integrin participates in tumor metastasis and autoimmune diseases. α4B Markedly inhibited α4 integrin-dependent cell adhesion through the cytoplasmic region of α4B. α4B Is a novel endogenous inhibitor of α4 integrin. This study provides a possible role of α4B as an inhibitor of α4 integrin-mediated metastasis.