Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.
The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Anutosh
A
Chakraborty
J Kent
JK
Werner
Michael A
MA
Koldobskiy
Asif K
AK
Mustafa
Krishna R
KR
Juluri
Joseph
J
Pietropaoli
Adele M
AM
Snowman
Solomon H
SH
Snyder
D020816:Amino Acid Motifs; D017209:Apoptosis; D047390:Casein Kinase II / Q000378:metabolism*; D002470:Cell Survival; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007333:Insulin Resistance; D009369:Neoplasms / Q000201:enzymology; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase
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