Calmodulin-dependent protein kinase IV regulates nuclear export of Cabin1 during T-cell activation.
Calcium signaling is critical for activation of T lymphocytes and has been proposed to be transduced through multiple calmodulin target proteins. Whereas the calcineurin-NFAT signaling module is critical for all mammalian T cells, the role of calmodulin-dependent kinase IV (CaMKIV) in mouse naïve CD4+ T-cell activation remains enigmatic. We have applied lentivius-mediated RNA interference of CaMKIV to human T cells and found that knockdown of CaMKIV abrogates T-cell receptor-mediated transcription of the IL-2 gene. We demonstrate that CaMKIV directly phosphorylates Cabin1, a transcriptional corepressor for myocyte enhancer factor 2, creating a docking site for 14-3-3, which causes its nuclear export. CaMKIV-mediated nuclear export of Cabin1 is likely to account for a significant part of the requirement of CaMKIV during human T-cell activation.
Pan
Fan
F
Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Means
Anthony R
AR
Liu
Jun O
JO
D048948:14-3-3 Proteins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D019703:Calcineurin / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology*; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D002147:Calmodulin; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007476:Ionophores; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D015759:Ionomycin; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D019703:Calcineurin