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Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4

Oncogene volume 25, pages 5071–5084 (2006)Cite this article

Abstract

Junctional adhesion molecule 4 (JAM4) is a cell adhesion molecule that interacts with a tight junction protein, membrane-associated guanylate kinase inverted 1 (MAGI-1). Our previous studies suggest that JAM4 is implicated in the regulation of paracellular permeability and the signalings of hepatocyte growth factor. In this study, we performed yeast two-hybrid screening to search for an unidentified JAM4-binding protein and obtained one isoform of Ligand-of-Numb protein X1 (LNX1), LNXp70, that is an interactor of Numb. Ligand-of-Numb protein X1 is expressed in kidney glomeruli and intestinal epithelial cells, where JAM4 is also detected. Immunoprecipitation from kidney lysates supports the in vivo interaction of proteins. Biochemical studies reveal that JAM4 directly binds the second PDZ domain of LNX1 through its carboxyl terminus. Junctional adhesion molecule 4, LNX1 and Numb form a tripartite complex in vitro and are partially colocalized in heterologous cells. Ligand-of-Numb protein X1 facilitates endocytosis of JAM4 and is involved in transforming growth factor β -induced redistribution of JAM4 in mammary epithelial cells. Experiments using dominant-negative constructs and RNA interference insure that Numb is necessary for the LNX1-mediated endocytosis of JAM4. All these findings indicate that LNX1 provides an endocytic scaffold for JAM4 that is implicated in the reorganization of cell junctions.

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Acknowledgements

This study was supported by grants-in-aids for Scientific Research (B) and on Priority Areas, and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, YASUDA Medical Research Foundation, and the Kao Foundation for Arts and Sciences. AK, AK and MI are supported by Tokyo Medical and Dental University 21st century COE program ‘brain integration and its disorders’. We thank K Miyazono (University of Tokyo) for NMuMG and Eph-4 cells and T Akiyama (University of Tokyo) for C57MG cells.

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  1. Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    A Kansaku, S Hirabayashi, H Mori, N Fujiwara, A Kawata, M Ikeda, C Rokukawa & Y Hata

  2. Department of Anatomy, Juntendo University School of Medicine, Tokyo, Japan

    H Kurihara

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  1. A Kansaku
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Correspondence to Y Hata.

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Kansaku, A., Hirabayashi, S., Mori, H. et al. Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4. Oncogene 25, 5071–5084 (2006). https://doi.org/10.1038/sj.onc.1209468

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