CDK2

CDK2 is a member of the Ser/Thr protein kinase family. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2. It is a catalytic subunit of the cyclin-dependent protein kinase complex, whose activity is restricted to the G1-S phase, and essential for cell cycle G1/S phase transition. Cdks (cyclin-dependent kinases) are heteromeric serine/threonine kinases that control progression through the cell cycle in concert with their regulatory subunits, the cyclins. Cdks are constitutively expressed and are regulated by several kinases and phosphastases, including Wee1, CDK-activating kinase and Cdc25 phosphatase. Although there are 12 different cdk genes, only 5 have been shown to directly drive the cell cycle (Cdk1, -2, -3, -4, and -6). Following extracellular mitogenic stimuli, cyclin D gene expression is upregulated. Cdk4 forms a complex with cyclin D and phosphorylates Rb protein, leading to liberation of the transcription factor E2F. E2F induces transcription of genes including cyclins A and E, DNA polymerase and thymidine kinase. Cdk4-cyclin E complexes form and initiate G1/S transition. Subsequently, Cdk1-cyclin B complexes form and induce G2/M phase transition.

CDK2 Related Areas

Cancer>>Cell Cycle>>Cyclin-Dependent Kinase(CDK)>>CDK2

Enzyme>>Protein Kinase>>Intracellular Kinase>>CDK2

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>CDK2

CDK2 Alternative Names

CDK2, p33(CDK2) [Homo sapiens]

Cdk2, A630093N05Rik [Mus musculus]

Summaries for CDK2

Entrez Gene summary for CDK2:

The protein encoded by CDK2 is a member of the Ser/Thr protein kinase family. This protein kinase is highly similar to CDK2 products of S. cerevisiae cdc28, and S. pombe cdc2. It is a catalytic subunit of the cyclin-dependent protein kinase complex, whose activity is restricted to the G1-S phase, and essential for cell cycle G1/S phase transition. CDK2 protein associates with and regulated by the regulatory subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A) and p27Kip1 (CDKN1B). Activity of CDK2 protein is also regulated by its protein phosphorylation. Two alternatively spliced variants and multiple transcription initiation sites of CDK2 have been reported.

Wikipedia summary for CDK2:

Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.

Human CDK2 Protein General Information

 

• Protein names: Cyclin-dependent kinase 2, Short name=CDK2
• Sequence length: 298 AA.
• Sequence similarities: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.
• Post-translational modification: Phosphorylated at Thr-160 by CDK7 in a CAK complex. Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.
• Subunit structure: Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC. Found in a complex with both SPDYA and CDKN1B/KIP1. Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1.
• Subcellular location: Cytoplasm › cytoskeleton › centrosome. Nucleus › Cajal body. Cytoplasm. Endosome. Note: Localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Nuclear-cytoplasmic trafficking is mediated during the inhibition by 1,25-(OH)2D3.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Enzyme regulation: Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it. CDK2 is inhibited by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. CDK2 is stimulated by MYC. CDK2 is inactivated by CDKN1A (p21).

General information above from UniProt

Function for CDK2 Protein

UniProtKB:

Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 .Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization.

Genatlas:

• complexing and phosphorylating with cyclin E (CCNE1) for the regulation of chromosome stability
• CDK2 leads to the initiation of centrosome duplication  
• CDK2 encodes a key regulator of the G1/S phase transition
• CDK2 has an activity upon SMAD3, its major physiologic substrate
• CDK2 phosphorylates the linker histone H1, thus providing a signal for the disassembly of higher order chromatin structure during interphase
• CDK2 phosphorylates FOXO1, resulte in cytoplasmic localization and inhibition of FOXO1 and regulate apoptotic cell death after DNA strand breakage
• CDK2 is involved in apoptosis upon its regulation by p21
• CDK2 phosphorylates RIalpha and thus promotes the dissociation of the RIalpha-RFC40 complex (Replication Factor C) and subsequently the association of the RFC40-RFC37 complex
• CDK2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation
• CDK2 phosphorylates BARD1 and consequently down-regulates the ubiquitin-ligase activity of BRCA1-BARD1
• CDK2 plays an essential role for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase
• CDK2 is the major regulator of S-phase entry
• CDK2 is dispensable for neural progenitor cells proliferation, differentiation and survival of adult-born dentate gyrus granule neurons
• CDK2 functions as a progesterone receptor coactivator
• CDK2 plays an important role in cell cycle regulation in embryonic stem cells that are likely to bear significant impacts on the maintenance of their pluripotent phenotype 
• CDK2 has a role in the G1 to S phase transition in embryonic stem cells
• S-phase CDK, uniquely controls the G2/M checkpoint that prevents cells with damaged DNA from initiating mitosis 
• CDK2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent TP53-independent G2/M checkpoint activation
• CDK2 is involved in CDK1 and CDK2-mediated phosphorylation, a key mechanism governing EZH2 function
• CDK2 promotes interphase nuclear pore complexes formation in human dividing cells 
• CDK2 controls cell cycle progression of oligodendrocyte progenitor cell
• CDK2 is dispensable for myelination but is important for adult oligodendrocyte progenitor cell renewal, and CDK2 could be one of the underlying mechanisms that drive adult progenitors to differentiate and thus regenerate myelin
• CDK1, CDK2, CDK5, can phosphorylate human DNMT1 at Ser154, suggesting an important role for CDKs in controlling DNA methylation patterns in mammalian cells

Homology for human CDK2

• ortholog to yeast S.cerevisiae cdc28
• ortholog to Cdk2, Mus musculus
• ortholog to Cdk2, Rattus norvegicus
• ortholog to cdk2, Pan troglodytes

Drugs for CDK2

Target	Drug Name	Disease	Drug Status
CDK2	SNS-032	B-lymphoid malignancies and advanced solid tumours	Phase I
CDK2	AT7519	Solid Tumors	Phase I
CDK2	AT7519	Non-Hodgkin's Lymphoma	Phase I/II
CDK2	Capridine-beta	Advanced Solid Tumors	Preclinical
CDK2	Flavopiridol	Hepatocellular Carcinoma	Discontinued
CDK2	Flavopiridol	Lymphoma	Phase II
CDK2	Flavopiridol	Chronic lymphocytic leukemia	Phase II
CDK2	Seliciclib	Advanced Solid Tumors	Phase I
CDK2	Seliciclib	Breast, NSCLC, lymphoid leukemia, glomerulonephritis & multiple myeloma	Terminated in Phase II
CDK2	Ro 31-7453	Ovarian Cancer; Endometrial Cancer	Phase II
CDK2	R547	Neoplasms, Advanced solid tumours	Phase I completed
CDK2	R-roscovitine	Non-Small Cell Lung Cancer (NSCLC)	Terminated in Phase II
CDK2	SCH 727965	Advanced solid tumours, NHL, multiple myeloma and CLL	Phase I
CDK2	SCH 727965	Advanced breast cancer, NSCLC, acute leukaemia and lymphoma	Phase II
CDK2	ZK 304709	Advanced solid tumours	Phase I

Drugs for CDK2 from TTD (Therapeutic Targets Database)