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.
Highlights
Down syndrome cell adhesion molecule (DSCAM),1 a novel member of the immunoglobulin superfamily, maps to the chromosome at 21q22.2–22.3
We show that human DSCAM directly interacts with Pak1
Human DSCAM Interacts with Pak—We investigated whether the mammalian DSCAM regulates Pak function
Summary
Down syndrome cell adhesion molecule (DSCAM), a novel member of the immunoglobulin superfamily, maps to the chromosome at 21q22.2–22.3. DSCAM is a type I transmembrane protein that likely functions as a cell surface receptor mediating axon growth and pathfinding [3,4,5,6]. Besides these important implications, little is know about the physiological function or the molecular mechanism of DSCAM signal transduction in mammalian systems. It has been found that ORNs frequently terminate in ectopic sites both within and outside the antennal lobe in Dscam mutants These observations indicate that Dscam plays an important role in neuronal axon guidance and axon bifurcation [7, 8, 10, 11]. Our studies suggest that the human DSCAM may have biological
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