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Vol. 17, Issue 5, 2465-2475, May 2006
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* Department of Biochemistry, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
Department of Orthopedics, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan
Submitted September 2, 2005;
Revised February 21, 2006;
Accepted February 27, 2006
Monitoring Editor: Asma Nusrat
The dynamic turnover of tight junctions (TJs) is essential for epithelial-mesenchymal transitions and/or mesenchymal-epithelial transitions during epithelial morphogenesis. We previously demonstrated that Rab13 specifically mediates the endocytic recycling of occludin. Here, we identified MICAL-L2 (molecule interacting with CasL-like 2) as a novel Rab13-binding protein. Immunoprecipitation and immunofluorescence microscopy showed that MICAL-L2 specifically bound to the GTP-bound form of Rab13 via its C terminus, which contained a coiled-coil domain, and localized at TJs in epithelial MTD-1A cells. Recycling assay demonstrated that a MICAL-L2 mutant lacking the Rab13-binding domain (MICAL-L2-N) specifically inhibited the endocytic recycling of occludin but not transferrin receptor. Ca2+ switch assay further revealed that MICAL-L2-N as well as Rab13 Q67L inhibited the recruitment of occludin to the plasma membrane, the development of transepithelial electrical resistance, and the formation of a paracellular diffusion barrier. MICAL-L2 was displaced from TJs upon actin depolymerization and was distributed along radiating actin cables and stress fibers in Ca2+-depleted MTD-1A and fibroblastic NIH3T3 cells, respectively. These results suggest that MICAL-L2 mediates the endocytic recycling of occludin and the formation of functional TJs by linking Rab13 to actin cytoskeleton. We rename MICAL-L2 as JRAB (junctional Rab13-binding protein).
Abbreviations used: CC, coiled-coil; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; PM, plasma membrane; TER, transepithelial electrical resistance; TfR, transferrin receptor; TJ, tight junction; ZO, zonula occludens.
Address correspondence to: Takuya Sasaki (sasaki{at}basic.med.tokushima-u.ac.jp).
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