Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability
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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.
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.
JournalCell Communication and Signaling
PubMed Central IDPMC3704924
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Except where otherwise noted, this item's license is described as This 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.
- Protein implicated in nonsyndromic mental retardation regulates protein kinase A (PKA) activity.
- Authors: Al-Tawashi A, Jung SY, Liu D, Su B, Qin J
- Issue date: 2012 Apr 27
- Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability.
- Authors: Zamarbide M, Mossa A, Muñoz-Llancao P, Wilkinson MK, Pond HL, Oaks AW, Manzini MC
- Issue date: 2018 Dec 27
- The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation.
- Authors: Basel-Vanagaite L, Attia R, Yahav M, Ferland RJ, Anteki L, Walsh CA, Olender T, Straussberg R, Magal N, Taub E, Drasinover V, Alkelai A, Bercovich D, Rechavi G, Simon AJ, Shohat M
- Issue date: 2006 Mar
- Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells.
- Authors: Liu H, Palmer D, Jimmo SL, Tilley DG, Dunkerley HA, Pang SC, Maurice DH
- Issue date: 2000 Aug 25
- CC2D1A, a DM14 and C2 domain protein, activates NF-kappaB through the canonical pathway.
- Authors: Zhao M, Li XD, Chen Z
- Issue date: 2010 Aug 6
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