Protein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activity

Handle URI:
http://hdl.handle.net/10754/334571
Title:
Protein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activity
Authors:
Al-Tawashi, Azza; Jung, Sung Yun; Liu, Dou; Su, Bing; Qin, Jun
Abstract:
Mutation of the coiled-coil and C2 domain-containing 1A (CC2D1A) gene, which encodes a C2 domain and DM14 domain-containing protein, has been linked to severe autosomal recessive nonsyndromic mental retardation. Using a mouse model that produces a truncated form of CC2D1A that lacks the C2 domain and three of the four DM14 domains, we show that CC2D1A is important for neuronal differentiation and brain development. CC2D1A mutant neurons are hypersensitive to stress and have a reduced capacitytoformdendritesandsynapsesinculture. Atthebiochemical level,CC2D1Atransduces signals to the cyclic adenosine 3?,5?-monophosphate (cAMP)-protein kinase A (PKA) pathway during neuronal cell differentiation. PKA activity is compromised, and the translocation of its catalytic subunit to the nucleus is also defective in CC2D1A mutant cells. Consistently, phosphorylation of the PKA target cAMP-responsive element-binding protein, at serine 133, is nearly abolished in CC2D1A mutant cells. The defects in cAMP/PKA signaling were observed in fibroblast, macrophage, and neuronal primary cells derived from the CC2D1A KO mice. CC2D1A associates with the cAMP-PKA complex following forskolin treatment and accumulates in vesicles or on the plasma membrane in wild-type cells, suggesting that CC2D1A may recruit the PKA complex to the membrane to facilitate signal transduction. Together, our data show that CC2D1A is an important regulator of the cAMP/PKA signaling pathway, which may be the underlying cause for impaired mental function in nonsyndromic mental retardation patients with CC2D1A mutation. 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Al-Tawashi A, Jung SY, Liu D, Su B, Qin J (2012) Protein Implicated in Nonsyndromic Mental Retardation Regulates Protein Kinase A (PKA) Activity. Journal of Biological Chemistry 287: 14644-14658. doi:10.1074/jbc.M111.261875.
Publisher:
American Society for Biochemistry and Molecular Biology
Journal:
Journal of Biological Chemistry
Issue Date:
28-Feb-2012
DOI:
10.1074/jbc.M111.261875
PubMed ID:
22375002
PubMed Central ID:
PMC3340277
Type:
Article
ISSN:
00219258
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorAl-Tawashi, Azzaen
dc.contributor.authorJung, Sung Yunen
dc.contributor.authorLiu, Douen
dc.contributor.authorSu, Bingen
dc.contributor.authorQin, Junen
dc.date.accessioned2014-11-11T14:30:09Z-
dc.date.available2014-11-11T14:30:09Z-
dc.date.issued2012-02-28en
dc.identifier.citationAl-Tawashi A, Jung SY, Liu D, Su B, Qin J (2012) Protein Implicated in Nonsyndromic Mental Retardation Regulates Protein Kinase A (PKA) Activity. Journal of Biological Chemistry 287: 14644-14658. doi:10.1074/jbc.M111.261875.en
dc.identifier.issn00219258en
dc.identifier.pmid22375002en
dc.identifier.doi10.1074/jbc.M111.261875en
dc.identifier.urihttp://hdl.handle.net/10754/334571en
dc.description.abstractMutation of the coiled-coil and C2 domain-containing 1A (CC2D1A) gene, which encodes a C2 domain and DM14 domain-containing protein, has been linked to severe autosomal recessive nonsyndromic mental retardation. Using a mouse model that produces a truncated form of CC2D1A that lacks the C2 domain and three of the four DM14 domains, we show that CC2D1A is important for neuronal differentiation and brain development. CC2D1A mutant neurons are hypersensitive to stress and have a reduced capacitytoformdendritesandsynapsesinculture. Atthebiochemical level,CC2D1Atransduces signals to the cyclic adenosine 3?,5?-monophosphate (cAMP)-protein kinase A (PKA) pathway during neuronal cell differentiation. PKA activity is compromised, and the translocation of its catalytic subunit to the nucleus is also defective in CC2D1A mutant cells. Consistently, phosphorylation of the PKA target cAMP-responsive element-binding protein, at serine 133, is nearly abolished in CC2D1A mutant cells. The defects in cAMP/PKA signaling were observed in fibroblast, macrophage, and neuronal primary cells derived from the CC2D1A KO mice. CC2D1A associates with the cAMP-PKA complex following forskolin treatment and accumulates in vesicles or on the plasma membrane in wild-type cells, suggesting that CC2D1A may recruit the PKA complex to the membrane to facilitate signal transduction. Together, our data show that CC2D1A is an important regulator of the cAMP/PKA signaling pathway, which may be the underlying cause for impaired mental function in nonsyndromic mental retardation patients with CC2D1A mutation. 2012 by The American Society for Biochemistry and Molecular Biology, Inc.en
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.rightsAuthor's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articlesen
dc.rightsArchived with thanks to Journal of Biological Chemistryen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/en
dc.subjectBrain developmenten
dc.subjectCatalytic subunitsen
dc.subjectCoiled coilen
dc.subjectCyclic adenosineen
dc.subjectDomain-containing proteinsen
dc.subjectElement-binding proteinsen
dc.subjectForskolinen
dc.subjectMental retardationen
dc.subjectMonophosphatesen
dc.subjectMouse modelsen
dc.subjectMutant cellsen
dc.subjectNeuronal cellen
dc.subjectNeuronal differentiationen
dc.subjectPrimary cellsen
dc.subjectProtein kinase Aen
dc.subjectSignaling pathwaysen
dc.subjectUnderlying causeen
dc.subjectWild-type cellsen
dc.subjectAmino acidsen
dc.subjectCell cultureen
dc.subjectCell membranesen
dc.subjectEnzymesen
dc.subjectGenesen
dc.subjectHandicapped personsen
dc.subjectMammalsen
dc.subjectPhosphorylationen
dc.subjectSignal transductionen
dc.subjectProteinsen
dc.subjectcyclic AMP dependent protein kinaseen
dc.subjectcyclic AMP responsive element binding proteinen
dc.subjectforskolinen
dc.subjectphosphatidic aciden
dc.subjectanimal cellen
dc.subjectanimal experimenten
dc.subjectanimal modelen
dc.subjectanimal tissueen
dc.subjectarticleen
dc.subjectbrain developmenten
dc.subjectcell mutanten
dc.subjectcell nucleusen
dc.subjectcellular stress responseen
dc.subjectcoiled coil and C2 domain containing 1A geneen
dc.subjectcontrolled studyen
dc.subjectdendriteen
dc.subjectdevelopmental geneen
dc.subjectenzyme active siteen
dc.subjectenzyme phosphorylationen
dc.subjectenzyme substrate complexen
dc.subjectfemaleen
dc.subjectfibroblasten
dc.subjectgene functionen
dc.subjectgene locationen
dc.subjectmacrophageen
dc.subjectmembrane bindingen
dc.subjectmental deficiencyen
dc.subjectmouseen
dc.subjectnerve cell differentiationen
dc.subjectnerve cell plasticityen
dc.subjectneuropathologyen
dc.subjectnonhumanen
dc.subjectpriority journalen
dc.subjectprotein targetingen
dc.subjectsignal transductionen
dc.subjectsynapseen
dc.subjectwild typeen
dc.subjectActive Transport, Cell Nucleusen
dc.subjectAnimalsen
dc.subjectBrainen
dc.subjectCell Lineen
dc.subjectCell Nucleusen
dc.subjectCyclic AMP-Dependent Protein Kinasesen
dc.subjectDNA-Binding Proteinsen
dc.subjectGenetic Diseases, Inbornen
dc.subjectHumansen
dc.subjectIntellectual Disabilityen
dc.subjectMiceen
dc.subjectMice, Knockouten
dc.subjectNerve Tissue Proteinsen
dc.subjectNeuronsen
dc.subjectProtein Structure, Tertiaryen
dc.subjectRepressor Proteinsen
dc.subjectResponse Elementsen
dc.subjectSignal Transductionen
dc.subjectMusen
dc.titleProtein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activityen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalJournal of Biological Chemistryen
dc.identifier.pmcidPMC3340277en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionCenter for Molecular Discovery, Verna and Marrs McLean Depts. of Biochem. and Molecular Biology and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, United Statesen
dc.contributor.institutionDepartment of Immunobiology and Program of Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06520, United Statesen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en

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