CDK2

Cyclin-dependent kinase 2 • UniProt accession P24941

Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis (PubMed:10499802, PubMed:10884347, PubMed:10995386, PubMed:10995387, PubMed:11051553, PubMed:11113184, PubMed:12944431, PubMed:15800615, PubMed:17495531, PubMed:19966300, PubMed:20935635, PubMed:21262353, PubMed:21596315, PubMed:28216226, PubMed:28666995). Phosphorylates CABLES1, CTNNB1, CDK2AP2, ERCC6, NBN, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, SUV39H1, EZH2 (PubMed:10499802, PubMed:10995386, PubMed:10995387, PubMed:11051553, PubMed:11113184, PubMed:12944431, PubMed:15800615, PubMed:19966300, PubMed:20935635, PubMed:21262353, PubMed:21596315, PubMed:24728993, PubMed:28216226). Triggers duplication of centrosomes and DNA (PubMed:11051553).

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 (PubMed:18372919, PubMed:19238148, PubMed:19561645). Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in embryonic stem cells (ESCs) (PubMed:18372919, PubMed:19238148, PubMed:19561645). 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 (PubMed:18372919, PubMed:19238148, PubMed:19561645).

EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing (PubMed:20935635). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC (PubMed:19966300). 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 (PubMed:15800615, PubMed:20195506, PubMed:21319273).

In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation (PubMed:15800615). Involved in regulation of telomere repair by mediating phosphorylation of NBN (PubMed:28216226). Phosphorylation of RB1 disturbs its interaction with E2F1 (PubMed:10499802).

NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication (PubMed:11051553). 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 (PubMed:10995386, PubMed:10995387). Required for vitamin D-mediated growth inhibition by being itself inactivated (PubMed:20147522).

Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner (PubMed:20079829). USP37 is activated by phosphorylation and thus triggers G1-S transition (PubMed:21596315). CTNNB1 phosphorylation regulates insulin internalization (PubMed:21262353).

Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Acts as a regulator of the phosphatidylinositol 3-kinase/protein kinase B signal transduction by mediating phosphorylation of the C-terminus of protein kinase B (PKB/AKT1 and PKB/AKT2), promoting its activation (PubMed:24670654)

Source: UniProt

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 (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995).

Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). 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. Interacts with CACUL1. May interact with CEP63.

Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:24670654, PubMed:8684460).

Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148)

Source: UniProt
Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, Nucleus, Cajal body, Cytoplasm, Endosome
Source: UniProt
  • G0 and Early G1
  • Telomere Extension By Telomerase
  • Activation of ATR in response to replication stress
  • Regulation of APC/C activators between G1/S and early anaphase
  • SCF(Skp2)-mediated degradation of p27/p21
  • Senescence-Associated Secretory Phenotype (SASP)
  • DNA Damage/Telomere Stress Induced Senescence
  • Processing of DNA double-strand break ends
  • TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
  • Regulation of TP53 Activity through Phosphorylation
  • Regulation of TP53 Degradation
  • G2 Phase
  • Orc1 removal from chromatin
  • Activation of the pre-replicative complex
  • CDK-mediated phosphorylation and removal of Cdc6
  • Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes
  • Cyclin E associated events during G1/S transition
  • Cyclin D associated events in G1
  • Cyclin A/B1/B2 associated events during G2/M transition
  • p53-Dependent G1 DNA Damage Response
  • Cyclin A:Cdk2-associated events at S phase entry
  • PTK6 Regulates Cell Cycle
  • Meiotic recombination
  • Transcriptional regulation of granulopoiesis
  • Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)
  • Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
  • Factors involved in megakaryocyte development and platelet production
Source: Reactome via UniProt

Mutations

No mutation information available.

Synthetic Lethal Network

Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to CDK2, aggregated across our SSL data sources. Click any partner node to view that gene’s page.

Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.

BioGRID SLOrth SynLethDB MexDrugs Multi-source
Sources: BioGRID, SLOrth, SynLethDB, MexDrugs

Clinical Trials

Total Trials Found: 19

NCT ID Condition Brief Title Phase Status
NCT03739554 Relapsed or Refractory Chronic Lymphocytic Leukemia CYC065 CDK Inhibitor and Venetoclax Study in Relapsed/Refractory CLL PHASE1 COMPLETED
NCT04017546 AML, MDS CYC065 CDK Inhibitor and Venetoclax Study in Relapsed/Refractory AML or MDS PHASE1 COMPLETED
NCT06950086 HR-positive, HER2-negative Advanced Breast Cancer Study of TYK-00540 Tablets in Patients With Advanced Solid Tumors PHASE1, PHASE2 RECRUITING
NCT06257264 Breast Cancer, Small Cell Lung Cancer, Ovarian Cancer, Gastric Cancer, Hormone-receptor-positive Breast Cancer, Hormone Receptor Positive HER-2 Negative Breast Cancer, Advanced Solid Tumor, Endometrial Cancer, Prostate Cancer, TNBC - Triple-Negative Breast Cancer, GastroEsophageal Cancer, Bladder Cancer A Study to Examine the Safety of Different Doses of BG-68501 Given to Participants With Advanced-Stage Tumors PHASE1 RECRUITING
NCT05431153 Healthy A Study to Investigate the Effect of Tablet Formulation and Food on PF-07104091 in Healthy Participants PHASE1 COMPLETED
NCT06264921 Solid Tumor, Solid Tumor, Adult, Advanced Solid Tumor, Metastatic Tumor, Ovarian Cancer, Ovarian Neoplasms, Ovarian Carcinoma, Metastatic Ovarian Carcinoma, Endometrial Cancer, Endometrial Neoplasms, Endometrial Diseases, Metastatic Endometrial Cancer, Metastatic Endometrial Carcinoma, Advanced Endometrial Carcinoma, Advanced Ovarian Carcinoma, Gastric Cancer, Advanced Gastric Carcinoma, Metastatic Gastric Cancer, Metastatic Gastric Carcinoma, Small-cell Lung Cancer, Small Cell Lung Carcinoma, Triple Negative Breast Cancer, Triple Negative Breast Neoplasms, Platinum-resistant Ovarian Cancer, Platinum-refractory Ovarian Carcinoma, CCNE1 Amplification, Hormone Receptor Negative Breast Carcinoma, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Progesterone-receptor-positive Breast Cancer A Study With NKT3447 for Adults With Advanced/Metastatic Solid Tumors PHASE1 TERMINATED
NCT07029399 HR+ Breast Cancer, Triple Negative Breast Cancer (TNBC), CCNE1 Amplified Advanced Solid Tumors, HR+ HER2- Breast Cancer, Ovarian Cancer, Endometrial Cancer, Uterine Carcinosarcoma A Study With NKT5097 for Adults With Advanced/Metastatic Solid Tumors PHASE1 RECRUITING
NCT05735080 Breast Cancer, Breast Cancer Metastatic, Hormone Receptor Positive Tumor, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Ovarian Cancer, CCNE1 Amplification, Solid Tumor, Advanced Cancer, Metastatic Cancer Open-Label Study to Evaluate the Safety, Tolerability, PK, and Efficacy of INX-315 in Patients With Advanced Cancer PHASE1, PHASE2 RECRUITING
NCT05905341 Breast Cancer, Ovarian Cancer, Liposarcoma, Non-small Cell Lung Cancer (NSCLC), Endometrial, Solid Tumors Study of PF-07224826, as a Single Agent or in Combination With Endocrine Therapy in Participants With Breast Cancer and Other Advanced Solid Tumors. PHASE1 WITHDRAWN
NCT05191017 Prostate Cancer, Prostatic Cancer, Cancer of Prostate, Cancer of the Prostate, Prostate Neoplasm, Castrate Resistant Prostate Cancer, Castration Resistant Prostatic Cancer, Castration Resistant Prostatic Neoplasms Study of NUV-422 in Combination With Enzalutamide in Patients With mCRPC PHASE1, PHASE2 WITHDRAWN