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J. Biol. Chem., Vol. 283, Issue 40, 27230-27238, October 3, 2008

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ABL2/ARG Tyrosine Kinase Mediates SEMA3F-induced RhoA Inactivation and Cytoskeleton Collapse in Human Glioma Cells^*

Akio Shimizu¹, Akiko Mammoto¹, Joseph E. Italiano, Jr.^¶, Elke Pravda, Andrew C. Dudley, Donald E. Ingber^||, and Michael Klagsbrun^||2

From the Vascular Biology Program and Departments of Surgery and ^||Pathology, Children's Hospital Boston and Harvard Medical School, and the ^¶Division of Translational Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

Class three semaphorins (SEMAs) were originally shown to be mediators of axon guidance that repelled axons and collapsed growth cones, but it is now evident that SEMA3F, for example, has similar effects on tumor cells and endothelial cells (EC). In both human U87MG glioma cells and human umbilical vein EC, SEMA3F induced rapid cytoskeletal collapse, suppressed cell contractility, decreased phosphorylation of cofilin, and inhibited cell migration in culture. Analysis of the signaling pathways showed that SEMA3F formed a complex with NRP2 (neuropilin-2) and plexin A1. These interactions eventually led to inactivation of the small GTPase, RhoA, which is necessary for stress fiber formation and cytoskeleton integrity. A novel upstream RhoA mediator was shown to be ABL2, also known as ARG, a membrane-anchored nonreceptor tyrosine kinase. Within minutes after the addition of SEMA3F, ABL2 directly bound plexin A1 but not to a plexin A1 mutant lacking the cytoplasmic domain. In addition, ABL2 phosphorylated and thereby activated p190RhoGAP, which inactivated RhoA (GTP to GDP), resulting in cytoskeleton collapse and inhibition of cell migration. On the other hand, cells overexpressing an ABL2 inactive kinase mutant or treated with ABL2 small interfering RNA did not inactivate RhoA. Cells treated with p190RhoGAP small interfering RNA also did not inactivate RhoA. Together, these results suggested that ABL2/ARG is a novel mediator of SEMA3F-induced RhoA inactivation and collapsing activity.

Received for publication, June 13, 2008 , and in revised form, July 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA37392 (to M. K.), CA45548 (to M. K. and D. I.), CA58833 (to D. I.), and HL068130 (to J. I.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Movies S1 and S2 and Figs. S1-S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Vascular Biology Program, Depts. of Surgery and Pathology, Children's Hospital Boston, Harvard Medical School, Karp Family Research Laboratories, 12.210, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2157; Fax: 617-730-0233; E-mail: michael.klagsbrun{at}childrens.harvard.edu.

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