Cyclin-dependent kinase 1

Cyclin-dependent kinase 1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1LC9, 4YC6
Identifiers
Symbols	CDK1 ; CDC2; CDC28A; P34CDC2
External IDs	OMIM: 116940 MGI: 88351 HomoloGene: 68203 ChEMBL: 308 GeneCards: CDK1 Gene
EC number	2.7.11.22, 2.7.11.23
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • cyclin-dependent protein serine/threonine kinase activity • protein binding • ATP binding • RNA polymerase II carboxy-terminal domain kinase activity • Hsp70 protein binding Cellular component • nucleus • nucleoplasm • cytoplasm • mitochondrion • centrosome • cytosol • spindle microtubule • membrane • midbody • extracellular exosome • mitotic spindle Biological process • G1/S transition of mitotic cell cycle • regulation of transcription involved in G1/S transition of mitotic cell cycle • G2/M transition of mitotic cell cycle • MAPK cascade • activation of MAPKK activity • activation of MAPK activity • microtubule cytoskeleton organization • mitotic cell cycle • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • DNA replication • DNA repair • apoptotic process • organelle organization • mitotic nuclear division • mitotic nuclear envelope disassembly • mitotic G2 DNA damage checkpoint • centrosome cycle • epidermal growth factor receptor signaling pathway • small GTPase mediated signal transduction • Ras protein signal transduction • pronuclear fusion • axon guidance • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • regulation of Schwann cell differentiation • cell migration • peptidyl-serine phosphorylation • peptidyl-threonine phosphorylation • epithelial cell differentiation • anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • protein localization to kinetochore • TRIF-dependent toll-like receptor signaling pathway • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • negative regulation of apoptotic process • innate immune response • regulation of embryonic development • vascular endothelial growth factor receptor signaling pathway • neurotrophin TRK receptor signaling pathway • cell division • stress-activated MAPK cascade • positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition • regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	983	12534
Ensembl	ENSG00000170312	ENSMUSG00000019942
UniProt	P06493	P11440
RefSeq (mRNA)	NM_001130829	NM_007659
RefSeq (protein)	NP_001163877	NP_031685
Location (UCSC)	Chr 10: 60.78 – 60.79 Mb	Chr 10: 69.34 – 69.35 Mb
PubMed search	[1]	[2]

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. In humans, Cdk1 is encoded by the CDC2 gene. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates (over 75 have been identified in budding yeast); phosphorylation of these proteins leads to cell cycle progression.

Structure

Crystal Structure of the human Cdk1 homolog, Cdk2

Cdk1 is a small protein (approximately 34 kilodaltons), and is highly conserved. The human homolog of Cdk1, CDC2, shares approximately 63% amino-acid identity with its yeast homolog. Furthermore, human CDC2 is capable of rescuing fission yeast carrying a cdc2 mutation. Cdk1 is comprised mostly by the bare protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which ATP fits. Substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the hydroxyl serine/threonine of the substrate.

In addition to this catalytic core, Cdk1, like other cyclin-dependent kinases, contains a T-loop, which, in the absence of an interacting cyclin, prevents substrate binding to the Cdk1 active site. Cdk1 also contains a PSTAIRE helix, which, upon cyclin binding, moves and rearranges the active site, facilitating Cdk1 kinase activities.

Function

Fig. 1 The diagram shows the role of Cdk1 in progression through the S. cerevisiae cell cycle. Cln3-Cdk1 leads to Cln1,2-Cdk1 activity, eventually resulting in Clb5,6-Cdk1 activity and then Clb1-4-Cdk1 activity.

When bound to its cyclin partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in S. cerevisaie, so Cdk1 S. cerevisiae activity is described here.

In the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF (SCB-binding factor) and MBF (MCB-binding factor). These two complexes control G₁/S gene transcription; however, they are normally inactive. SBF is inhibited by the protein Whi5; however, when phosphorylated by Cln3-Cdk1, Whi5 is ejected from the nucleus, allowing for transcription of the G₁/S regulon, which includes the G₁/S cyclins Cln1,2. G₁/S cyclin-Cdk1 activity leads to preparation for S phase entry (e.g., duplication of centromeres or the spindle pole body), and a rise in the S cyclins (Clb5,6 in S. cerevisiae). Clb5,6-Cdk1 complexes directly lead to replication origin initiation; however, they are inhibited by Sic1, preventing premature S phase initiation.

Cln1,2 and/or Clb5,6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins (e.g., Clb1, 2, 3 and 4) in complex with Cdk1 leads to spindle assembly and sister chromatid alignment. Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APC^Cdc20, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the final events of mitosis (e.g., spindle disassembly, mitotic exit).

Regulation

Given its essential role in cell cycle progression, Cdk1 is highly regulated. Most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the active site of Cdk1, allowing for Cdk1 activity; furthermore, cyclins impart specificity to Cdk1 activity. At least some cyclins contain a hydrophobic patch which may directly interact with substrates, conferring target specificity. Furthermore, cyclins can target Cdk1 to particular subcellular locations.

In addition to regulation by cyclins, Cdk1 is regulated by phosphorylation. A conserved tyrosine (Tyr15 in humans) leads to inhibition of Cdk1; this phosphorylation is thought to alter ATP orientation, preventing efficient kinase activity. In S. pombe, for example, incomplete DNA synthesis may lead to stabilization of this phosphorylation, preventing mitotic progression. Wee1, conserved among all eukaryotes phosphorylates Tyr15, whereas members of the Cdc25 family are phosphatases, counteracting this activity. The balance between the two is thought to help govern cell cycle progression. Wee1 is controlled upstream by Cdr1, Cdr2, and Pom1.

Cdk1-cyclin complexes are also governed by direct binding of Cdk inhibitor proteins (CKIs). One such protein, already discussed, is Sic1. Sic1 is a stoichiometric inhibitor that binds directly to Clb5,6-Cdk1 complexes. Multisite phosphorylation, by Cdk1-Cln1/2, of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry. Only until Sic1 inhibition is overcome can Clb5,6 activity occur and S phase initiation may begin.

Interactions

Cdk1 has been shown to interact with:

• BCL2,
• CCNB1,
• CCNE1,
• CDKN3
• DAB2,
• FANCC,
• GADD45A,
• LATS1,
• LYN,
• P53, and
• UBC.

See also

• E2F#E2F.2FpRb complexes
• Hyperphosphorylation
• cdc25
• Maturation promoting factor
• CDK
• cyclin A
• cyclin B
• cyclin D
• cyclin E
• Wee (cell cycle)