Research Papers:

Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF

Tatsushi Yoshida, Masatsune Tsujioka, Shinya Honda, Masato Tanaka and Shigeomi Shimizu _

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Oncotarget. 2016; 7:34420-34429. https://doi.org/10.18632/oncotarget.8883

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Tatsushi Yoshida1,3,*, Masatsune Tsujioka1,*, Shinya Honda1,*, Masato Tanaka2, Shigeomi Shimizu1

1Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

2Laboratory of Immune Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan

3Present affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

*These authors have contributed equally to this work

Correspondence to:

Shigeomi Shimizu, email: [email protected]

Keywords: migration, autophagy, GEF-H1

Received: September 14, 2015     Accepted: April 02, 2016     Published: April 21, 2016


Cell migration is a process crucial for a variety of biological events, such as morphogenesis and wound healing. Several reports have described the possible regulation of cell migration by autophagy; however, this remains controversial. We here demonstrate that mouse embryonic fibroblasts (MEFs) lacking autophagy protein 5 (Atg5), an essential molecule of autophagy, moved faster than wild-type (WT) MEFs. Similar results were obtained for MEFs lacking Atg7 and unc-51-like kinase 1 (Ulk1), which are molecules required for autophagy. This phenotype was also observed in Atg7-deficient macrophages. WT MEFs moved by mesenchymal-type migration, whereas Atg5 knockout (KO) MEFs moved by amoeba-like migration. This difference was thought to be mediated by the level of RhoA activity, because Atg5 KO MEFs had higher RhoA activity, and treatment with a RhoA inhibitor altered Atg5 KO MEF migration from the amoeba type to the mesenchymal type. Autophagic regulation of RhoA activity was dependent on GEF-H1, a member of the RhoA family of guanine nucleotide exchange factors. In WT MEFs, GEF-H1 directly bound to p62 and was degraded by autophagy, resulting in low RhoA activity. In contrast, the loss of autophagy increased GEF-H1 levels and thereby activated RhoA, which caused cells to move by amoeba-like migration. This amoeba-like migration was cancelled by the silencing of GEF-H1. These results indicate that autophagy plays a role in the regulation of migration by degrading GEF-H1.

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