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Hafner, M., Schmitz, A., Grune, I., Srivatsan, S.G., Paul, B., Kolanus, W., Quast, T., Kremmer, E., Bauer, I. and Famulok, M. (2006) Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature, 444, 941-944. doi:10.1038/nature05415

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• TITLE: The polybasic region of cytohesin-2 determines paxillin binding specificity to mediate cell migration

  AUTHORS: Tomohiro Torii, Yuki Miyamoto, Kohji Nishimura, Masahiro Maeda, Akito Tanoue, Junji Yamauchi

  KEYWORDS: Cytohesin-2; Polybasic Region; Paxillin; Migration

  JOURNAL NAME: Advances in Biological Chemistry, Vol.2 No.3, August 23, 2012

  ABSTRACT: The intracellular signaling pathways through ADP-ribosylation factors (Arfs) of the small GTPase family control cell morphological changes by regulating membrane components and/or cytoskeletal protein dynamics. We previously reported that cytohesin-2 (CYTH2), an Arf-guanine-nucleotide exchange factor (GEF), binds to the cytoskeletal scaffold protein paxillin through C-terminal region of CYTH2 and promotes the migration of mouse 3T3-L1 fibroblasts. In mammals, CYTH family GEFs are composed of four subfamilies. Among them, CYTH2 and CYTH3 are widely expressed in tissues and it remains to be clarified to determine whether they have specific biochemical and cellular functions or are redundant. Here, we show that the C-terminal short polybasic region of CYTH2 is necessary and sufficient for binding to paxillin to mediate cell migration. Although 3T3-L1 cells primarily express CYTH2 and CYTH3 of four CYTH family members, neither knockdown of CYTH3 by the specific siRNA nor expression of its C-terminal region inhibits migration. Importantly, replacing the C-terminal region of CYTH3 with that of CYTH2 adds the ability of paxillinbinding and mediating migration to CYTH3. Conversely, replacing the C- terminal region of CYTH2 with that of CYTH3 leads to loss of these abilities of CYTH2. These results reveal that paxillin is a unique binding partner with CYTH2 in migrating cells, presenting the first CYTH family GEF’s region that is involved in the selectivity of the binding protein.