title: Phosphorylation of doublecortin by protein kinase A orchestrates microtubule and actin dynamics to promote neuronal progenitor cell migration.
abstract: Doublecortin (DCX) is a microtubule-associated protein that is specifically expressed in neuronal cells. Genetic mutation of DCX causes lissencephaly disease. Although the abnormal cortical lamination in lissencephaly is thought to be attributable to neuronal cell migration defects, the regulatory mechanisms governing interactions between DCX and cytoskeleton in the migration of neuronal progenitor cells remain obscure. In this study we found that the G(s) and protein kinase A (PKA) signal elicited by pituitary adenylate cyclase-activating polypeptide promotes neuronal progenitor cells migration. Stimulation of G(s)-PKA signaling prevented microtubule bundling and induced the dissociation of DCX from microtubules in cells. PKA phosphorylated DCX at Ser-47, and the phospho-mimicking mutant DCX-S47E promoted cell migration. Activation of PKA and DCX-S47E induced lamellipodium formation. Pituitary adenylate cyclase-activating polypeptide and DCX-S47E stimulated the activation of Rac1, and DCX-S47E interacted with Asef2, a guanine nucleotide exchange factor for Rac1. Our data reveal a dual reciprocal role for DCX phosphorylation in the regulation of microtubule and actin dynamics that is indispensable for proper brain lamination.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Toriyama
authors.forename: Norikazu
authors.initials: N
authors.lastname: Mizuno
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukami
authors.forename: Tokuichi
authors.initials: T
authors.lastname: Iguchi
authors.forename: Michinori
authors.initials: M
authors.lastname: Toriyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000502:physiology*; D058953:Neural Stem Cells / Q000166:cytology* / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D009479:Neuropeptides / Q000378:metabolism*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: C495402:Adcyap1 protein, mouse; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C484602:Rac1 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein