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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
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
-
In Vitro Techniques
-
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*
Substances
-
DNA-Binding Proteins
-
Drosophila Proteins
-
Hedgehog Proteins
-
Proto-Oncogene Proteins
-
Transcription Factors
-
Wnt Proteins
-
Zebrafish Proteins
-
ci protein, Drosophila
-
hh protein, Drosophila
-
Protein Kinases
-
Glycogen Synthase Kinases
-
Casein Kinases
-
Protein-Serine-Threonine Kinases
-
Sgg protein, Drosophila
-
Cyclic AMP-Dependent Protein Kinases
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Glycogen Synthase Kinase 3