Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1.
T cell activation requires the import of NF-AT transcription factors to the nucleus, a process promoted by calcineurin-dependent dephosphorylation and inhibited by poorly understood protein kinases. Here, we report the identification of two protein kinases that oppose NF-AT4 nuclear import. Casein kinase Ialpha directly binds and phosphorylates NF-AT4, resulting in the inhibiton of NF-AT4 nuclear translocation. MEKK1 indirectly suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and CKIalpha. CKIalpha thus acts to establish an intramolecular masking of the nuclear location signal on NF-AT4, while MEKK1 augments this mechanism, and may further provide a link to signal transduction pathways regulating NF-AT4.
Zhu
J
J
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Shibasaki
F
F
Price
R
R
Guillemot
J C
JC
Yano
T
T
Dötsch
V
V
Wagner
G
G
Ferrara
P
P
McKeon
F
F
D000595:Amino Acid Sequence; D001692:Biological Transport; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D047388:Casein Kinases; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D014157:Transcription Factors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D047388:Casein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases