Phosphorylation by Double-Time/CKIε and CKIα Targets Cubitus Interruptus for Slimb/β-TRCP-Mediated Proteolytic Processing
Copyright policy )Phosphorylation by Double-Time/CKIε and CKIα Targets Cubitus Interruptus for Slimb/β-TRCP-Mediated Proteolytic Processing
Hedgehog (Hh) proteins govern animal development by regulating the Gli/Ci family of transcription factors. In Drosophila, Hh signaling blocks proteolytic processing of full-length Ci to generate a truncated repressor form. Ci processing requires sequential phosphorylation by PKA, GSK3, and a casein kinase I (CKI) family member(s). Here we show that Double-time (DBT)/CKIepsilon and CKIalpha act in conjunction to promote Ci processing. CKI phosphorylates Ci at three clusters of serine residues primed by PKA and GSK3 phosphorylation. CKI phosphorylation of Ci confers binding to the F-box protein Slimb/beta-TRCP, the substrate recognition component of the SCF(Slimb/beta-TRCP) ubiquitin ligase required for Ci processing. CKI phosphorylation sites act cooperatively to promote Ci processing in vivo. Substitution of Ci phosphorylation clusters with a canonical Slimb/beta-TRCP recognition motif in beta-catenin renders Slimb/beta-TRCP binding and Ci processing independent of CKI. We propose that phosphorylation of Ci by CKI creates multiple Slimb/beta-TRCP binding sites that act cooperatively to recruit SCF(Slimb/beta-TRCP).
- The University of Texas System United States
- Institute of Science Tokyo Japan
- The University of Texas Southwestern Medical Center United States
- The University of Texas Medical Branch at Galveston United States
- Department of Pharmacology University of Texas Southwestern Medical Center at Dallas United States
Sequence Homology, Amino Acid, Casein Kinase 1 epsilon, Ubiquitin-Protein Ligases, Molecular Sequence Data, Casein Kinase Ialpha, Cell Cycle Proteins, beta-Transducin Repeat-Containing Proteins, Cyclic AMP-Dependent Protein Kinases, Zinc Finger Protein GLI1, Animals, Genetically Modified, DNA-Binding Proteins, Glycogen Synthase Kinase 3, Drosophila melanogaster, Animals, Drosophila Proteins, Amino Acid Sequence, Phosphorylation, Protein Processing, Post-Translational, Developmental Biology, Peptide Hydrolases, Transcription Factors
Sequence Homology, Amino Acid, Casein Kinase 1 epsilon, Ubiquitin-Protein Ligases, Molecular Sequence Data, Casein Kinase Ialpha, Cell Cycle Proteins, beta-Transducin Repeat-Containing Proteins, Cyclic AMP-Dependent Protein Kinases, Zinc Finger Protein GLI1, Animals, Genetically Modified, DNA-Binding Proteins, Glycogen Synthase Kinase 3, Drosophila melanogaster, Animals, Drosophila Proteins, Amino Acid Sequence, Phosphorylation, Protein Processing, Post-Translational, Developmental Biology, Peptide Hydrolases, Transcription Factors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).127 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!