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J. Biol. Chem., Vol. 282, Issue 8, 5327-5339, February 23, 2007

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Src Signaling Regulates Completion of Abscission in Cytokinesis through ERK/MAPK Activation at the Midbody^*

From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan

Src family non-receptor-type tyrosine kinases regulate a wide variety of cellular events including cell cycle progression in G₂/M phase. Here, we show that Src signaling regulates the terminal step in cytokinesis called abscission in HeLa cells. Abscission failure with an unusually elongated intercellular bridge containing the midbody is induced by treatment with the chemical Src inhibitors PP2 and SU6656 or expression of membrane-anchored Csk chimeras. By anti-phosphotyrosine immunofluorescence and live cell imaging, completion of abscission requires Src-mediated tyrosine phosphorylation during early stages of mitosis (before cleavage furrow formation), which is subsequently delivered to the midbody through Rab11-driven vesicle transport. Treatment with U0126, a MEK inhibitor, decreases tyrosine phosphorylation levels at the midbody, leading to abscission failure. Activated ERK by MEK-catalyzed dual phosphorylation on threonine and tyrosine residues in the TEY sequence, which is strongly detected by anti-phosphotyrosine antibody, is transported to the midbody in a Rab11-dependent manner. Src kinase activity during the early mitosis mediates ERK activation in late cytokinesis, indicating that Src-mediated signaling for abscission is spatially and temporally transmitted. Thus, these results suggest that recruitment of activated ERK, which is phosphorylated by MEK downstream of Src kinases, to the midbody plays an important role in completion of abscission.

Received for publication, August 31, 2006 , and in revised form, December 18, 2006.

^* This work was supported in part by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, a research grant from the Takeda Science Foundation, and a research grant from Graduate School of Pharmaceutical Sciences, Chiba University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Japanese Society for the Promotion of Science Research Fellow for Young Scientists.

² To whom correspondence should be addressed: Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan. Tel./Fax: 81-43-226-2868; E-mail: nyama{at}p.chiba-u.ac.jp.

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