Phosphorylation by double-time/CKIε and CKIα targets Cubitus Interruptus for Slimb/β-TRCP-mediated proteolytic processing

Jianhang Jia, Lei Zhang, Qing Zhang, Chao Tong, Bing Wang, Fajian Hou, Kazuhito Amanai, Jin Jiang

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


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)/CKIε and CKIα 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/β-TRCP, the substrate recognition component of the SCFSlimb/β-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/β-TRCP recognition motif in β-catenin renders Slimb/β-TRCP binding and Ci processing independent of CKI. We propose that phosphorylation of Ci by CKI creates multiple Slimb/β-TRCP binding sites that act cooperatively to recruit SCFSlimb/β-TRCP.

Original languageEnglish
Pages (from-to)819-830
Number of pages12
JournalDevelopmental Cell
Issue number6
StatePublished - Dec 2005

Bibliographical note

Funding Information:
We thank Liping Luo for excellent technical assistance, Dr. Markus Noll for dco mutant stocks, and Dr. D.M. Virshup for CKIε antibody. This work was supported by grants from the NIH, Welch Foundation, and Leukemia and Lymphoma Society Scholar Program to J. Jiang. J. Jiang is the Eugene McDermott Endowed Scholar in Biomedical Science at UT Southwestern Medical Center.

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology


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