HIPK family kinases bind and regulate the function of the CCR4-NOT complex.
The serine/threonine kinase HIPK2 functions as a regulator of developmental processes and as a signal integrator of a wide variety of stress signals, such as DNA damage, hypoxia, and reactive oxygen intermediates. Because the kinase is generated in a constitutively active form, its expression levels are restricted by a variety of different mechanisms. Here we identify the CCR4-NOT complex as a new regulator of HIPK2 abundance. Down-regulation or knockout of the CCR4-NOT complex member CNOT2 leads to reduced HIPK2 protein levels without affecting the expression level of HIPK1 or HIPK3. A fraction of all HIPK family members associates with the CCR4-NOT components CNOT2 and CNOT3. HIPKs also phosphorylate the CCR4-NOT complex, a feature that is shared with their yeast progenitor kinase, YAK1. Functional assays reveal that HIPK2 and HIPK1 restrict CNOT2-dependent mRNA decay. HIPKs are well known regulators of transcription, but the mutual regulation between CCR4-NOT and HIPKs extends the regulatory potential of these kinases by enabling posttranscriptional gene regulation.
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.
Alfonso
A
Rodriguez-Gil
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.
Olesja
O
Ritter
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.
Juliane
J
Hornung
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.
Hilda
H
Stekman
Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
Marcus
M
Krüger
Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
Thomas
T
Braun
Institute of Molecular Immunology, Helmholtz Center Munich, German Research Center for Environmental Health, D-81377 Munich; Germany.
Elisabeth
E
Kremmer
Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.
Michael
M
Kracht
Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany lienhard.schmitz@biochemie.med.uni-giessen.de.
M Lienhard
ML
Schmitz
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D054398:Receptors, CCR4 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
C515354:CCR4 protein, human; C485365:CNOT2 protein, human; C466622:CNOT3 protein, human; D002352:Carrier Proteins; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D054398:Receptors, CCR4; D012097:Repressor Proteins; D014157:Transcription Factors; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases