Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Junko
J
Odajima
Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Siddharth
http://orcid.org/0000-0002-2813-9536
S
Saini
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Piotr
P
Jung
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
Yasmine
Y
Ndassa-Colday
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
Scott
S
Ficaro
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Yan
Y
Geng
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.
Eugenio
E
Marco
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Wojciech
W
Michowski
Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Yaoyu E
YE
Wang
Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
James A
JA
DeCaprio
Department of Internal Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Larisa
L
Litovchick
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
Jarrod
J
Marto
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Piotr
P
Sicinski
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics* / Q000378:metabolism; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D060066:Protein Interaction Maps / Q000235:genetics; D040901:Proteomics; D016196:S Phase / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000378:metabolism
C503689:Ccne2 protein, mouse; D019927:Cyclin E; D016213:Cyclins; D015513:Oncogene Proteins; C568314:cyclin E1, mouse; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2