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PLoS Genet. 2016 Nov 9;12(11):e1006429. doi: 10.1371/journal.pgen.1006429. eCollection 2016 Nov.

Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
2
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
3
Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
4
Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
6
Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

E-type cyclins (cyclins E1 and E2) are components of the cell cycle machinery that has been conserved from yeast to humans. The major function of E-type cyclins is to drive cell division. It is unknown whether in addition to their 'core' cell cycle functions, E-type cyclins also perform unique tissue-specific roles. Here, we applied high-throughput mass spectrometric analyses of mouse organs to define the repertoire of cyclin E protein partners in vivo. We found that cyclin E interacts with distinct sets of proteins in different compartments. These cyclin E interactors are highly enriched for phosphorylation targets of cyclin E and its catalytic partner, the cyclin-dependent kinase 2 (Cdk2). Among cyclin E interactors we identified several novel tissue-specific substrates of cyclin E-Cdk2 kinase. In proliferating compartments, cyclin E-Cdk2 phosphorylates Lin proteins within the DREAM complex. In the testes, cyclin E-Cdk2 phosphorylates Mybl1 and Dmrtc2, two meiotic transcription factors that represent key regulators of spermatogenesis. In embryonic and adult brains cyclin E interacts with proteins involved in neurogenesis, while in adult brains also with proteins regulating microtubule-based processes and microtubule cytoskeleton. We also used quantitative proteomics to demonstrate re-wiring of the cyclin E interactome upon ablation of Cdk2. This approach can be used to study how protein interactome changes during development or in any pathological state such as aging or cancer.

PMID:
27828963
PMCID:
PMC5102403
DOI:
10.1371/journal.pgen.1006429
[Indexed for MEDLINE]
Free PMC Article

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