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PMID:20307497
| Citation |
Kim, EA, Kim, JE, Sung, KS, Choi, DW, Lee, BJ and Choi, CY (2010) Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for phosphorylation and proteasomal degradation. Biochem. Biophys. Res. Commun. 394:966-71 |
|---|---|
| Abstract |
The regulation of intracellular beta-catenin levels is central in the Wnt/beta-catenin signaling cascade and the activation of the Wnt target genes. Here, we show that homeodomain-interacting protein kinase 2 (HIPK2) acts as a negative regulator of the Wnt/beta-catenin pathway. Knock-down of endogenous HIPK2 increases the stability of beta-catenin and results in the accumulation of beta-catenin in the nucleus, consequently enhancing the expression of Wnt target genes and cell proliferation both in vivo and in cultured cells. HIPK2 inhibits TCF/LEF-mediated target gene activation via degradation of beta-catenin. HIPK2 phosphorylates beta-catenin at its Ser33 and Ser37 residues without the aid of a priming kinase. Substitutions of Ser33 and Ser37 for alanines abolished the degradation of beta-catenin associated with HIPK2. In ex vivo mouse model, HIPK2 knock-down resulted in accumulation of beta-catenin, thereby potentiated beta-catenin-mediated cell proliferation and tumor formation. Furthermore, the axis duplication induced by the ectopic expression of beta-catenin was blocked by co-injection of HIPK2 mRNAs into Xenopus embryos. Taken together, HIPK2 appears to function as a novel negative regulator of beta-catenin through its phosphorylation and proteasomal degradation. |
| Links |
PubMed Online version:10.1016/j.bbrc.2010.03.099 |
| Keywords |
Amino Acid Substitution; Animals; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line, Tumor; Gene Knockdown Techniques; Humans; Mice; Mice, Inbred BALB C; Phosphorylation; Proteasome Endopeptidase Complex/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Two-Hybrid System Techniques; Wnt Proteins/metabolism; Xenopus; beta Catenin/metabolism |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0019900 : kinase binding |
ECO:0000021: |
UniProtKB:Q9H2X6
|
F |
figure S1 |
complete | |||
| GO:0005634 : nucleus |
ECO:0000314: |
C |
figure 1E |
complete | ||||
| GO:0005737 : cytoplasm |
ECO:0000314: |
C |
figure 1E |
complete | ||||
| GO:0016310 : phosphorylation |
ECO:0000315: |
P |
figure 3C |
complete | ||||
| GO:0005515 : protein binding |
ECO:0000021: |
UniProtKB:P35222
|
F |
figure S1 |
complete | |||
| GO:0045449 : regulation of transcription |
ECO:0000315: |
P |
figure 2 |
complete | ||||
| GO:0031647 : regulation of protein stability |
ECO:0000315: |
P |
figure 1D |
complete | ||||
| GO:0051246 : regulation of protein metabolic process |
ECO:0000315: |
P |
figure 1E |
complete | ||||
| GO:0030111 : regulation of Wnt receptor signaling pathway |
ECO:0000315: |
P |
figure 2A |
complete | ||||
| GO:0060828 : regulation of canonical Wnt receptor signaling pathway |
ECO:0000315: |
P |
figure 2 |
complete | ||||
| GO:0016310 : phosphorylation |
ECO:0000314: |
P |
figure 3B |
complete | ||||
| GO:0008283 : cell proliferation |
ECO:0000315: |
P |
figure 4C |
complete | ||||
| GO:0010629: negative regulation of gene expression |
ECO:0000315: |
P |
figure 4D |
complete | ||||
See also
References
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