CASK phosphorylation by PKA regulates the protein-protein interactions of CASK and expression of the NMDAR2b gene

J. Neurochem. (2010) 112, 1562-1573. Calcium/calmodulin-dependent serine kinase (CASK), a causative gene in X-linked mental retardation, acts as a multi-domain scaffold protein and interacts with more than 20 cellular proteins in different subcellular regions of neurons. It is of interest, therefore...

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Published in:Journal of neurochemistry 2010-03, Vol.112 (6), p.1562-1573
Main Authors: Huang, Tzyy-Nan, Chang, Hui-Ping, Hsueh, Yi-Ping
Format: Article
Language:English
Subjects:
Adult and adolescent clinical studies
Animals
Biological and medical sciences
Brain - cytology
Brain - metabolism
Calcium
calcium/calmodulin-dependent serine kinase
Cell Line
Cricetinae
Cricetulus
Cyclic AMP - metabolism
Cyclic AMP - pharmacology
Cyclic AMP-Dependent Protein Kinases - metabolism
Cyclic AMP-Dependent Protein Kinases - pharmacology
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Disks Large Homolog 4 Protein
Enzyme Inhibitors - pharmacology
Gene Expression Regulation - drug effects
Genes
Guanylate Kinases - genetics
Guanylate Kinases - metabolism
Immunoprecipitation
Intellectual deficiency
Intellectual disabilities
Intracellular Signaling Peptides and Proteins - metabolism
Isoquinolines - pharmacology
Kinases
Medical sciences
Membrane Proteins - metabolism
Mutagenesis, Site-Directed - methods
Mutation - genetics
Nerve Tissue Proteins - metabolism
Neuroblastoma
Neurology
Neurons - drug effects
Neurons - metabolism
NMDA receptor
Phosphoproteins - metabolism
Phosphorylation - drug effects
protein kinase A phosphorylation
Proteins
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Rats
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Serine - metabolism
Signal Transduction - drug effects
Signal Transduction - physiology
Sulfonamides - pharmacology
Syndecan-2 - metabolism
T-Box Domain Proteins - metabolism
T-brain-1
Tetrodotoxin - pharmacology
Threonine - genetics
Threonine - metabolism
Transfection - methods
Up-Regulation - drug effects
Zonula Occludens-1 Protein
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Summary:J. Neurochem. (2010) 112, 1562-1573. Calcium/calmodulin-dependent serine kinase (CASK), a causative gene in X-linked mental retardation, acts as a multi-domain scaffold protein and interacts with more than 20 cellular proteins in different subcellular regions of neurons. It is of interest, therefore, to explore whether post-translational modification regulates CASK's protein-protein interactions. Here, we provide evidence that CASK is phosphorylated by protein kinase A (PKA), identifying residue S562 in the PSD-95-Dlg-ZO-1 domain and residue T724 in the guanylate kinase domain as PKA sites by an in vitro PKA kinase reaction and site-directed mutagenesis. Although the role of S562 phosphorylation is not clear, T724 phosphorylation up-regulates the interaction between CASK and T-box transcription factor T-brain-1 (Tbr-1). NMDAR2b, a downstream target of the CASK-Tbr-1 complex, was then used to explore the significance of CASK phosphorylation by PKA. In cultured cortical neurons, the PKA pathway stimulates both the protein expression and the promoter activity of NMDAR2b. Deletion of the Tbr-1-binding sites greatly reduces the 3′-5′-cyclic AMP responsiveness of the NMDAR2b promoter, and the CASK T724A mutation does not promote the 3′-5′-cyclic AMP responsiveness of NMDAR2b. In conclusion, our data provide evidence that PKA phosphorylates CASK, regulates the nuclear function of CASK, and consequently modulates NMDAR2b expression.
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2010.06569.x