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First published online February 22, 2006
doi: 10.1242/10.1242/jcs.02797

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Elmo1 inhibits ubiquitylation of Dock180

Yoshinori Makino¹, Masumi Tsuda¹, Shin Ichihara¹, Takuya Watanabe¹, Mieko Sakai¹, Hirofumi Sawa^1,*, Kazuo Nagashima¹, Shigetsugu Hatakeyama² and Shinya Tanaka^1,

¹ Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, N15, W7, Sapporo 060-8638, Japan
² Department of Molecular Biochemistry, Hokkaido University Graduate School of Medicine, N15, W7, Sapporo 060-8638, Japan

Author for correspondence (e-mail: tanaka{at}med.hokudai.ac.jp)

Accepted 15 November 2005

Dock180, a member of the CDM family of proteins, plays roles in biological processes such as phagocytosis and motility through its association with the signalling adaptor protein Crk. Recently, the complex formation between Dock180 and Elmo1 was reported to function as a bipartite guanine nucleotide exchange factor for Rac. In this study, we demonstrated that the amount of Dock180 increased when Elmo1 was co-expressed. Dock180 was found to be ubiquitylated and Dock180 protein levels could be augmented by treatment with proteasome inhibitor. The ubiquitylation of Dock180 was enhanced by epidermal growth factor (EGF), Crk and adhesion-dependent signals. Furthermore, Elmo1 inhibited ubiquitylation of Dock180, resulting in the increase in Dock180 levels. The Elmo1 mutant 531, which encompasses amino acids required for Dock180 binding, preserved the inhibitory effects on ubiquitylation of Dock180. Upon EGF stimulation, both Dock180 and ubiquitin were demonstrated to translocate to the cell periphery by immunofluorescence, and we found ubiquitylation of Dock180 and its inhibition by Elmo1 to occur in cellular membrane fractions by in vivo ubiquitylation assay. These data suggest that Dock180 is ubiquitylated on the plasma membrane, and also that Elmo1 functions as an inhibitor of ubiquitylation of Dock180. Therefore, an ubiquitin-proteasome-dependent protein degradation mechanism might contribute to the local activation of Rac on the plasma membrane.

Key words: Dock180, Elmo1, Crk, Rac, Ubiquitylation

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