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PMID: 15546612 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.

Molecular cell ·Vol. 16 ·No. 4 ·2004-11-19 ·Pages 509-20

Fryer CJ, White JB, Jones KA

Abstract

Notch signaling releases the Notch receptor intracellular domain (ICD), which complexes with CBF1 and Mastermind (MAM) to activate responsive genes. We previously reported that MAM interacts with CBP/p300 and promotes hyperphosphorylation and degradation of the Notch ICD in vivo. Here we show that CycC:CDK8 and CycT1:CDK9/P-TEFb are recruited with Notch and associated coactivators (MAM, SKIP) to the HES1 promoter in signaling cells. MAM interacts directly with CDK8 and can cause it to localize to subnuclear foci. Purified recombinant CycC:CDK8 phosphorylates the Notch ICD within the TAD and PEST domains, and expression of CycC:CDK8 strongly enhances Notch ICD hyperphosphorylation and PEST-dependent degradation by the Fbw7/Sel10 ubiquitin ligase in vivo. Point mutations affecting conserved Ser residues within the ICD PEST motif prevent hyperphosphorylation by CycC:CDK8 and stabilize the ICD in vivo. These findings suggest a role for MAM and CycC:CDK8 in the turnover of the Notch enhancer complex at target genes.

MeSH Terms

Adaptor Proteins, Signal Transducing/metabolism Animals Basic Helix-Loop-Helix Transcription Factors Blotting, Western Cell Line, Tumor Chromatin/metabolism Coculture Techniques Cyclin-Dependent Kinase 8 Cyclin-Dependent Kinase 9/metabolism Cyclin-Dependent Kinases/metabolism DNA-Binding Proteins/metabolism Drosophila Proteins/metabolism Enhancer Elements, Genetic Genes, Reporter HeLa Cells Homeodomain Proteins/metabolism Humans L Cells Luciferases/metabolism Membrane Proteins/chemistry,metabolism Mice Nuclear Proteins/metabolism Osteosarcoma/pathology Phosphorylation Point Mutation Precipitin Tests Promoter Regions, Genetic Protein Structure, Tertiary Receptors, Notch Signal Transduction Trans-Activators Transcription Factor HES-1 Transcription Factors Transcriptional Activation Transforming Growth Factor beta/metabolism Ubiquitin-Protein Ligases/metabolism

Chemicals

Adaptor Proteins, Signal Transducing Basic Helix-Loop-Helix Transcription Factors Chromatin DNA-Binding Proteins Drosophila Proteins Homeodomain Proteins MAML1 protein, human Membrane Proteins Nuclear Proteins Receptors, Notch SPHKAP protein, human Trans-Activators Transcription Factor HES-1 Transcription Factors Transforming Growth Factor beta HES1 protein, human Luciferases Ubiquitin-Protein Ligases CDK8 protein, human CDK9 protein, human Cdk8 protein, Drosophila Cyclin-Dependent Kinase 8 Cyclin-Dependent Kinase 9 Cyclin-Dependent Kinases

Authors & Affiliations

3 authors, click to expand affiliations / ORCID

Fryer Christy J

Regulatory Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

White J Brandon

Jones Katherine A

Article Info

Journal

Molecular cell

Abbr.

Mol Cell

ISSN

1097-2765

DOI

10.1016/j.molcel.2004.10.014

Published

2004-11-19

Pages

509-20

Language

English

Region

United States

NLM ID

9802571

Subset

Grants

NIGMS NIH HHS · GM067127 · United States

NCI NIH HHS · P01CA54418 · United States

External Links

PubMed source DOI: 10.1016/j.molcel.2004.10.014 View journal details

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Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.

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