title: Rab13 acts downstream of the kinase Mst1 to deliver the integrin LFA-1 to the cell surface for lymphocyte trafficking.
abstract: In lymphocytes, the kinase Mst1 is required for the proper organization of integrins in the plasma membrane at the leading edge of migrating cells, which is critical for lymphocyte trafficking. We found a functional link between the small G protein Rab13 and Mst1 in lymphocyte adhesion and migration. In response to stimulation of T lymphocytes with chemokine, Mst1 promoted phosphorylation of the guanine nucleotide exchange factor DENND1C (differentially expressed in normal and neoplastic cells domain 1C), which activated Rab13. Active Rab13 associated with Mst1 to facilitate the delivery of the integrin LFA-1 (lymphocyte function-associated antigen 1) to the leading edge of lymphocytes. Delivery of LFA-1 involved the recruitment of myosin Va along actin filaments, which extended as a result of the localization of the actin regulatory protein VASP to the cell periphery through phosphorylation of VASP at Ser(157) by Mst1. Inhibition of Rab13 function reduced the adhesion and migration of lymphocytes on ICAM-1 (intercellular adhesion molecule-1), the ligand for LFA-1, and inhibited the formation of a ring-like arrangement of LFA-1 at the contact sites between T cells and antigen-presenting cells. The lymphoid tissues of Rab13-deficient mice had reduced numbers of lymphocytes because of the defective trafficking capability of these cells. These results suggest that Rab13 acts with Mst1 to regulate the spatial distribution of LFA-1 and the motility and trafficking of lymphocytes.
authors: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan.
authors: Akihiko
authors: A
authors: Nishikimi
authors: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan.
authors: Sayaka
authors: S
authors: Ishihara
authors: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan.
authors: Madoka
authors: M
authors: Ozawa
authors: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors: Kan
authors: K
authors: Etoh
authors: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors: Mitsunori
authors: M
authors: Fukuda
authors: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan. CREST, Japan Science and Technology Agency, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
authors: Tatsuo
authors: T
authors: Kinashi
authors: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan. CREST, Japan Science and Technology Agency, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan. katagirk@kitasato-u.ac.jp.
authors: Koko
authors: K
authors: Katagiri
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D021381:Protein Transport / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C000596151:DENND1C protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016169:Lymphocyte Function-Associated Antigen-1; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C484177:Rab13 protein, mouse; D020691:rab GTP-Binding Proteins