title: The cytoplasmic adaptor protein Caskin mediates Lar signal transduction during Drosophila motor axon guidance.
abstract: The multiprotein complexes that receive and transmit axon pathfinding cues during development are essential to circuit generation. Here, we identify and characterize the Drosophila sterile α-motif (SAM) domain-containing protein Caskin, which shares homology with vertebrate Caskin, a CASK [calcium/calmodulin-(CaM)-activated serine-threonine kinase]-interacting protein. Drosophila caskin (ckn) is necessary for embryonic motor axon pathfinding and interacts genetically and physically with the leukocyte common antigen-related (Lar) receptor protein tyrosine phosphatase. In vivo and in vitro analyses of a panel of ckn loss-of-function alleles indicate that the N-terminal SAM domain of Ckn mediates its interaction with Lar. Like Caskin, Liprin-α is a neuronal adaptor protein that interacts with Lar via a SAM domain-mediated interaction. We present evidence that Lar does not bind Caskin and Liprin-α concurrently, suggesting they may assemble functionally distinct signaling complexes on Lar. Furthermore, a vertebrate Caskin homolog interacts with LAR family members, arguing that the role of ckn in Lar signal transduction is evolutionarily conserved. Last, we characterize several ckn mutants that retain Lar binding yet display guidance defects, implying the existence of additional Ckn binding partners. Indeed, we identify the SH2/SH3 adaptor protein Dock as a second Caskin-binding protein and find that Caskin binds Lar and Dock through distinct domains. Furthermore, whereas ckn has a nonredundant function in Lar-dependent signaling during motor axon targeting, ckn and dock have overlapping roles in axon outgrowth in the CNS. Together, these studies identify caskin as a neuronal adaptor protein required for axon growth and guidance.
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors: Yi-Lan
authors: YL
authors: Weng
authors: Nan
authors: N
authors: Liu
authors: Aaron
authors: A
authors: DiAntonio
authors: Heather T
authors: HT
authors: Broihier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology*; D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology*; D004525:Efferent Pathways / Q000166:cytology / Q000502:physiology; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009046:Motor Neurons / Q000502:physiology*; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D054557:Receptor-Like Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D029721:Drosophila Proteins; D009153:Mutagens; D009419:Nerve Tissue Proteins; C558400:ckn protein, Drosophila; D012313:RNA; D005020:Ethyl Methanesulfonate; D005982:Glutathione Transferase; C117978:Lar protein, Drosophila; D054557:Receptor-Like Protein Tyrosine Phosphatases