title: PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1.
abstract: Nuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE-like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite outgrowth. NDE1/LIS1/NDEL1 interacts with Disrupted in Schizophrenia 1 (DISC1) and the cAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by cAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions, which we confirm experimentally. DISC1-PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1-PDE4 modulated and likely to regulate its neural functions.
authors.affiliation: Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. n.j.bradshaw@ed.ac.uk
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bradshaw
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.forename: Becky C
authors.initials: BC
authors.lastname: Carlyle
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ogawa
authors.forename: Hazel
authors.initials: H
authors.lastname: Davidson-Smith
authors.forename: Sheila
authors.initials: S
authors.lastname: Christie
authors.forename: Shaun
authors.initials: S
authors.lastname: Mackie
authors.forename: Pippa A
authors.initials: PA
authors.lastname: Thomson
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: J Kirsty
authors.initials: JK
authors.lastname: Millar
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D057907:Post-Synaptic Density / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D002352:Carrier Proteins; C412476:DISC1 protein, human; D008869:Microtubule-Associated Proteins; C421108:NDEL1 protein, human; C525094:Nde1 protein, human; D009419:Nerve Tissue Proteins; D013912:Threonine; D017868:Cyclic AMP-Dependent Protein Kinases; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human