Function
CDK1, also known as Cell Division Cycle Protein 2, plays a pivotal role in regulating the eukaryotic cell cycle by modulating the centrosome cycle and mitotic onset. It promotes the G2-M transition, regulates G1 progression and G1-S transition through interaction with multiple interphase cyclins. CDK1 is essential in higher cells for entry into the S-phase and mitosis.
CDK1 acts as a kinase, phosphorylating a broad range of substrates, including:
* **Cell Cycle Regulation:** PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2, and RUNX2.
* **Early Embryonic Development:** The CDK1/CDC2-cyclin-B complex controls pronuclear union in interphase fertilized eggs and is essential for early embryonic development.
* **Mitotic Progression:** During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes, leading to the phosphorylation of various substrates that trigger events like centrosome separation, Golgi dynamics, nuclear envelope breakdown, and chromosome condensation. Once chromosomes are aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation, allowing for sister chromatid separation, chromosome decondensation, nuclear envelope reformation, and cytokinesis.
* **DNA Damage Response:** In response to DNA damage, CDK1 is inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation, halting cell cycle progression and genome replication at the G2 checkpoint, facilitating DNA repair. After successful DNA repair, WIP1-dependent signaling reactivates CDK1 through CDC25A/B/C-mediated dephosphorylation, resuming cell cycle progression.
* **Apoptosis Regulation:** In proliferating cells, CDK1-mediated FOXO1 phosphorylation during the G2-M phase represses FOXO1 interaction with 14-3-3 proteins, promoting FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of Bcl-xL/BCL2L1 following prolonged G2 arrest upon DNA damage triggers apoptosis. Conversely, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis, observed in cancer cell lines, breast tissues, and lymphocytes.
* **Epigenetic Regulation:** EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing.
* **Cell Migration:** CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration.
* **Centrosome Dynamics:** The CDK1-cyclin-B complex phosphorylates NCKAP5L, mediating its dissociation from centrosomes during mitosis.
* **Circadian Rhythm:** CDK1 regulates the cyclic expression of the core clock gene ARNTL/BMAL1 by phosphorylating its transcriptional repressor NR1D1. This phosphorylation is crucial for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1.
* **Microtubule Dynamics:** CDK1 phosphorylates EML3 at 'Thr-881', essential for its interaction with the HAUS augmin-like complex and TUBG1, influencing microtubule dynamics during mitosis.
* **Viral Infection:** CDK1 acts as a receptor for hepatitis C virus (HCV) in hepatocytes, facilitating its cell entry.