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J. Biol. Chem., Vol. 279, Issue 31, 32824-32831, July 30, 2004

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The Down Syndrome Cell Adhesion Molecule (DSCAM) Interacts with and Activates Pak^*

Weiquan Li and Kun-Liang Guan¶||

From the Life Sciences Institute, Department of Biological Chemistry, ^¶Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109

The Down syndrome cell adhesion molecule (DSCAM) is a member of the immunoglobulin superfamily that maps to a Down syndrome region of chromosome 21q22.2-22.3. In Drosophila, Dscam functions as an axon guidance receptor regulating targeting and branching. Genetic and biochemical studies have shown that in Drosophila, Dscam activates Pak1 via the Dock adaptor molecule. The extracellular domain of human DSCAM is highly homologous to the Drosophila protein; however, the intracellular domains of both human and Drosophila DSCAM share no obvious sequence identity. To study the signaling mechanisms of human DSCAM, we investigated the interaction between DSCAM and potential downstream molecules. We found that DSCAM directly binds to Pak1 and stimulates Pak1 phosphorylation and activity, unlike Drosophila where an adaptor protein Dock mediates the interaction between Dscam and Pak1. We also observed that DSCAM activates both JNK and p38 MAP kinases. Furthermore, expression of the cytoplasmic domain of DSCAM induces a morphological change in cultured cells that is JNK-dependent. These observations suggest that human DSCAM also signals through Pak1 and may function in axon guidance similar to the Drosophila Dscam.

Received for publication, February 20, 2004 , and in revised form, May 6, 2004.

^* This work was supported by grants from the National Institutes of Health (to K. L. G.). The costs of publication of this article were de-frayed 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. E-mail: kunliang{at}umich.edu.

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