Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability

Handle URI:
http://hdl.handle.net/10754/325259
Title:
Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability
Authors:
Altawashi, Azza; Gehring, Christoph A. ( 0000-0003-4355-4591 )
Abstract:
Background: Cyclic adenosine 3?5?-monophosphate (cAMP) is a key regulator of many cellular processes, including in the neuronal system, and its activity is tuned by Phosphodiesterase (PDE) activation. Further, the CC2D1A protein, consisting of N-Terminal containing four DM14 domains and C-terminal containing C2 domain, was shown to regulate the cAMP-PKA pathway. A human deletion mutation lacking the fourth DM14 and the adjacent C2 domain results in Non Syndromic Intellectual Disability (NSID) also referred to as Non Syndromic Mental Retardation (NSMR). Findings. Here we demonstrate that in Mouse Embryonic Fibroblasts (MEF) CC2D1A co-localizes with PDE4D in the cytosol before cAMP stimulation and on the periphery after stimulation, and that the movement to the periphery requires the full-length CC2D1A. In CC2D1A mouse mutant cells, the absence of three of the four DM14 domains abolishes migration of the complex to the periphery and causes constitutive phosphorylation of PDE4D Serine 126 (Sssup126esup) via the cAMP-dependent protein kinase A (PKA) resulting in PDE4D hyperactivity. Suppressing PDE4D activity with Rolipram in turn restores the down-stream phosphorylation of the "cAMP response element-binding protein" (CREB) that is defective in mouse mutant cells. Conclusion: Our findings suggest that CC2D1A is a novel regulator of PDE4D. CC2D1A interacts directly with PDE4D regulating its activity and thereby fine-tuning cAMP-dependent downstream signaling. Based on our in vitro evidence we propose a model which links CC2D1A structure and function to cAMP homeostasis thereby affecting CREB phosphorylation. We speculate that CC2D1A and/or PDE4D may be promising targets for therapeutic interventions in many disorders with impaired PDE4D function such as NSID. 2013 Al-Tawashi and Gehring; licensee BioMed Central Ltd.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Al-Tawashi A, Gehring C (2013) Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. Cell Communication and Signaling 11: 47. doi:10.1186/1478-811X-11-47.
Publisher:
Springer Nature
Journal:
Cell Communication and Signaling
Issue Date:
4-Jul-2013
DOI:
10.1186/1478-811X-11-47
PubMed ID:
23826796
PubMed Central ID:
PMC3704924
Type:
Article
ISSN:
1478811X
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorAltawashi, Azzaen
dc.contributor.authorGehring, Christoph A.en
dc.date.accessioned2014-08-27T09:43:01Z-
dc.date.available2014-08-27T09:43:01Z-
dc.date.issued2013-07-04en
dc.identifier.citationAl-Tawashi A, Gehring C (2013) Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. Cell Communication and Signaling 11: 47. doi:10.1186/1478-811X-11-47.en
dc.identifier.issn1478811Xen
dc.identifier.pmid23826796en
dc.identifier.doi10.1186/1478-811X-11-47en
dc.identifier.urihttp://hdl.handle.net/10754/325259en
dc.description.abstractBackground: Cyclic adenosine 3?5?-monophosphate (cAMP) is a key regulator of many cellular processes, including in the neuronal system, and its activity is tuned by Phosphodiesterase (PDE) activation. Further, the CC2D1A protein, consisting of N-Terminal containing four DM14 domains and C-terminal containing C2 domain, was shown to regulate the cAMP-PKA pathway. A human deletion mutation lacking the fourth DM14 and the adjacent C2 domain results in Non Syndromic Intellectual Disability (NSID) also referred to as Non Syndromic Mental Retardation (NSMR). Findings. Here we demonstrate that in Mouse Embryonic Fibroblasts (MEF) CC2D1A co-localizes with PDE4D in the cytosol before cAMP stimulation and on the periphery after stimulation, and that the movement to the periphery requires the full-length CC2D1A. In CC2D1A mouse mutant cells, the absence of three of the four DM14 domains abolishes migration of the complex to the periphery and causes constitutive phosphorylation of PDE4D Serine 126 (Sssup126esup) via the cAMP-dependent protein kinase A (PKA) resulting in PDE4D hyperactivity. Suppressing PDE4D activity with Rolipram in turn restores the down-stream phosphorylation of the "cAMP response element-binding protein" (CREB) that is defective in mouse mutant cells. Conclusion: Our findings suggest that CC2D1A is a novel regulator of PDE4D. CC2D1A interacts directly with PDE4D regulating its activity and thereby fine-tuning cAMP-dependent downstream signaling. Based on our in vitro evidence we propose a model which links CC2D1A structure and function to cAMP homeostasis thereby affecting CREB phosphorylation. We speculate that CC2D1A and/or PDE4D may be promising targets for therapeutic interventions in many disorders with impaired PDE4D function such as NSID. 2013 Al-Tawashi and Gehring; licensee BioMed Central Ltd.en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en
dc.subjectcAMP-PKA pathwayen
dc.subjectCC2D1Aen
dc.subjectNon-syndromic intellectual disabilityen
dc.subjectPhosphodiesterase activityen
dc.subjectCC2D1A proteinen
dc.subjectcyclic AMPen
dc.subjectcyclic AMP dependent protein kinaseen
dc.subjectcyclic AMP responsive element binding proteinen
dc.subjectphosphodiesteraseen
dc.subjectphosphodiesterase 4Den
dc.subjectregulator proteinen
dc.subjectrolipramen
dc.subjectunclassified drugen
dc.subjectanimal cellen
dc.subjectcellular distributionen
dc.subjectcontrolled studyen
dc.subjectcytosolen
dc.subjectembryoen
dc.subjectenzyme activityen
dc.subjectintellectual impairmenten
dc.subjectmouseen
dc.subjectnon syndromic intellectual disabilityen
dc.subjectprotein domainen
dc.subjectprotein localizationen
dc.subjectprotein phosphorylationen
dc.subjectprotein protein interactionen
dc.subjectprotein structureen
dc.titlePhosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disabilityen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalCell Communication and Signalingen
dc.identifier.pmcidPMC3704924en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionCenter for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 77030 Houston, TX, United Statesen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorGehring, Christoph A.en
kaust.authorAltawashi, Azzaen

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