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HIPK family kinases bind and regulate the function of the CCR4-NOT complex.

Rodriguez-Gil A, Ritter O, Hornung J, Stekman H, Krüger M, Braun T, Kremmer E, Kracht M, Schmitz ML
Molecular biology of the cell 2017; 271220160615: 1969-80


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.

Zugehörigkeit: Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Member of the German Center for Lung Research, D-35392 Giessen, Germany.

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