PMID:11955435

Citation	Price, MA and Kalderon, D (2002) Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108:823-35
Abstract	The secreted signaling molecule Hedgehog regulates gene expression in target cells in part by preventing proteolysis of the full-length Cubitus interruptus (Ci-155) transcriptional activator to the Ci-75 repressor form. Ci-155 proteolysis depends on phosphorylation at three sites by Protein Kinase A (PKA). We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. Ci-155 proteolysis is also inhibited if cells lack activity of the Drosophila GSK3, Shaggy, previously implicated in Wingless signaling. Conversely, Ci-155 levels are reduced in Hedgehog-responding cells by overexpression of PKA and the Drosophila CK1, Double-time, a regulator of circadian rhythms.
Links	PubMed
Keywords	Amino Acid Sequence; Animals; Binding Sites; Calcium-Calmodulin-Dependent Protein Kinases/genetics; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Casein Kinases; Cyclic AMP-Dependent Protein Kinases/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Drosophila; Drosophila Proteins/metabolism; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Hedgehog Proteins; Molecular Sequence Data; Mutation; Phosphorylation; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins/metabolism; Signal Transduction/physiology; Transcription Factors; Wnt Proteins; Zebrafish Proteins
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