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PMID:19088090

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Citation

Lee, W, Swarup, S, Chen, J, Ishitani, T and Verheyen, EM (2009) Homeodomain-interacting protein kinases (Hipks) promote Wnt/Wg signaling through stabilization of beta-catenin/Arm and stimulation of target gene expression. Development 136:241-51

Abstract

The Wnt/Wingless (Wg) pathway represents a conserved signaling cascade involved in diverse biological processes. Misregulation of Wnt/Wg signal transduction has profound effects on development. Homeodomain-interacting protein kinases (Hipks) represent a novel family of serine/threonine kinases. Members of this group (in particular Hipk2) are implicated as important factors in transcriptional regulation to control cell growth, apoptosis and development. Here, we provide genetic and phenotypic evidence that the sole Drosophila member of this family, Hipk, functions as a positive regulator in the Wg pathway. Expression of hipk in the wing rescues loss of the Wg signal, whereas loss of hipk can enhance decreased wg signaling phenotypes. Furthermore, loss of hipk leads to diminished Arm protein levels, whereas overexpression of hipk promotes the Wg signal by stabilizing Arm, resulting in activation of Wg responsive targets. In Wg transcriptional assays, Hipk enhanced Tcf/Arm-mediated gene expression in a kinase-dependent manner. In addition, Hipk can bind to Arm and Drosophila Tcf, and phosphorylate Arm. Using both in vitro and in vivo assays, Hipk was found to promote the stabilization of Arm. We observe similar molecular interactions between Lef1/beta-catenin and vertebrate Hipk2, suggesting a direct and conserved role for Hipk proteins in promoting Wnt signaling.

Links

PubMed Online version:10.1242/dev.025460

Keywords

Animals; Animals, Genetically Modified; Armadillo Domain Proteins/metabolism; Body Patterning/genetics; Body Patterning/physiology; Drosophila/genetics; Drosophila/growth & development; Drosophila/metabolism; Drosophila Proteins/metabolism; Female; Gene Expression Regulation, Developmental; Genes, Insect; Male; Models, Biological; Multiprotein Complexes; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; Repressor Proteins/metabolism; Signal Transduction; Transcription Factors/metabolism; Wing/growth & development; Wing/metabolism; Wnt Proteins/metabolism; Wnt1 Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:ARM

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0035142

F

Seeded From UniProt

complete

DROME:PANG1

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0035142

F

Seeded From UniProt

complete

DROME:PANG2

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0035142

F

Seeded From UniProt

complete

DROME:Q9W0Q1

enables

GO:0008013: beta-catenin binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0000117

F

Seeded From UniProt

complete

DROME:Q9W0Q1

enables

GO:0008134: transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0085432

F

Seeded From UniProt

complete

DROME:Q9W0Q1

involved_in

GO:0008587: imaginal disc-derived wing margin morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W0Q1

involved_in

GO:0008586: imaginal disc-derived wing vein morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W0Q1

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W0Q1

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q9W0Q1

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W0Q1

involved_in

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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