Cyclin-dependent kinase 11p110 and casein kinase 2 (CK2) inhibit the interaction between tyrosine hydroxylase and 14-3-3.
Tyrosine hydroxylase (TH) is regulated by the reversible phosphorylation of serines 8, 19, 31 and 40. Upon initiation of this study, serine 19 was unique due to its requirement of 14-3-3 binding after phosphorylation for optimal enzyme activity, although it has been more recently demonstrated that phosphorylated serine 40 also binds 14-3-3. To identify proteins that interact with TH following phosphorylation of serine 19, this amino acid was mutated to alanine and THS19A was used as bait in a yeast two-hybrid system. From this, mouse-derived cyclin-dependent kinase 11 (CDK11)p110 was identified as an interacting partner with THS19A. The interaction was confirmed using human CDK11p110 cDNA in a mammalian system. Previous research has demonstrated that casein kinase 2 (CK2) interacts with CDK11p110, and both were observed to phosphorylate TH in vitro. In addition, CDK11p110 overexpression was observed to inhibit the interaction between TH and 14-3-3. A mechanism contributing to disruption of the interaction between TH and 14-3-3 may be due to CK2 phosphorylation of specific 14-3-3 isoforms, i.e. 14-3-3 tau. Collectively, these results imply that CDK11p110 and CK2 negatively regulate TH catecholamine biosynthetic activity since phosphoserine 19 of TH requires 14-3-3 binding for optimal enzyme activity and a decreased rate of dephosphorylation.
Sachs
Nancy A
NA
Department of Pharmacology and Toxicology, The University of Arizona, College of Pharmacy, Tucson, Arizona 85721, USA.
Vaillancourt
Richard R
RR
D048948:14-3-3 Proteins; D019943:Amino Acid Substitution; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D047390:Casein Kinase II; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D018411:Spodoptera; D020798:Two-Hybrid System Techniques; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D014446:Tyrosine 3-Monooxygenase; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C447612:CDK11a protein, human; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases