title: The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak.
abstract: 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.
authors.affiliation: Life Sciences Institute, Department of Biological Chemistry, Institute of Gerontology, University of Michigan, Ann Arbor, 48109, USA.
authors.forename: Weiquan
authors.initials: W
authors.lastname: Li
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D019556:COS Cells; D015815:Cell Adhesion Molecules; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015815:Cell Adhesion Molecules; C110833:DSCAM protein, human; D029721:Drosophila Proteins; C491736:Dscam1 protein, Drosophila; D008565:Membrane Proteins; D011506:Proteins; D004247:DNA; D005982:Glutathione Transferase; C099277:Pak protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases