Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK.
In the human kinome, vaccinia-related kinase-1 (VRK1) is a new Ser-Thr kinase associated with proliferating tissues. VRK1 colocalizes with ATF2 in the nucleus and can form a stable complex. We have studied the phosphorylation of the transcription factor ATF2, which regulates gene expression by forming dimers with proteins with basic region-leucine zipper domains and recognizing cAMP-response element or AP1 sequences implicated in cellular responses to stress. VRK1 phosphorylates ATF2 mainly on Thr-73, stabilizing the ATF2 protein and increasing its intracellular level. Mutagenesis studies showed that Thr-73 and Ser-62 are implicated in ATF2 transcriptional activation by VRK1 detected in a functional assay based on ATF2 dimerization. VRK1 can activate the collagenase gene promoter that is regulated by ATF2 in a dose-dependent manner. Loss of kinase activity (K179E mutant) or the T73A substitution in ATF2 prevents both its accumulation and activation of transcription. VRK1 and JNK, which phosphorylates ATF2 in Thr-69 and Thr-71, have an additive effect on ATF2-dependent transcription at suboptimal doses. Therefore, two groups of amino acids in the ATF2 amino-terminal region can integrate different cellular signals mediated by at least five different kinases. VRK1 is an element of a novel signaling pathway that regulates gene transcription.
Sevilla
Ana
A
Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Santos
Claudio R
CR
Vega
Francisco M
FM
Lazo
Pedro A
PA
D051698:Activating Transcription Factor 2; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D013912:Threonine; D012694:Serine; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017364:Collagenases