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J. Biol. Chem., Vol. 280, Issue 12, 11361-11368, March 25, 2005

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Doublecortin Association with Actin Filaments Is Regulated by Neurabin II^*

Miki Tsukada, Alexander Prokscha, Ernst Ungewickell¶, and Gregor Eichele

From the Max Planck Institute for Experimental Endocrinology, Feodor-Lynen-Strasse 7, D-30625 Hannover, Germany and the ^¶Department of Cell Biology in the Center of Anatomy, Hannover Medical School, D-30623 Hannover, Germany

Mutations in the human Doublecortin (DCX) gene cause X-linked lissencephaly, a neuronal migration disorder affecting the neocortex and characterized by mental retardation and epilepsy. Because dynamic cellular asymmetries such as those seen in cell migration critically depend on a cooperation between the microtubule and actin cytoskeletal filament systems, we investigated whether Dcx, a microtubule-associated protein, is engaged in cytoskeletal cross-talk. We now demonstrate that Dcx co-sediments with actin filaments (F-actin), and using light and electron microscopy and spin down assays, we show that Dcx induces bundling and cross-linking of microtubules and F-actin in vitro. It has recently been shown that binding of Dcx to microtubules is negatively regulated by phosphorylation of the Dcx at Ser-47 or Ser-297. Although the phosphomimetic green fluorescent protein (GFP)-Dcx^S47E transfected into COS-7 cells had a reduced affinity for microtubules, we found that pseudophosphorylation was not sufficient to cause Dcx to bind to F-actin. When cells were co-transfected with neurabin II, a protein that binds F-actin as well as Dcx, GFP-Dcx and to an even greater extent GFP-Dcx^S47E became predominantly associated with filamentous actin. Thus Dcx phosphorylation and neurabin II combinatorially enhance Dcx binding to F-actin. Our findings raise the possibility that Dcx acts as a molecular link between microtubule and actin cytoskeletal filaments that is regulated by phosphorylation and neurabin II.

Received for publication, May 18, 2004 , and in revised form, October 27, 2004.

^* This work was supported by the Max-Planck-Society. 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.

To whom correspondence should be addressed. Tel.: 0511-5359-116; Fax: 0511-5359-186; E-mail: miki.tsukada{at}mpihan.mpg.de.

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