Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

CHEK2 (O96017) - Overview - Molecular Target Synopsis

Protein


CHEK2, Serine/threonine-protein kinase Chk2
Enzyme Classification 2.7.11.1
UniProt O96017

Also Known as CHK2_HUMAN, CHEK2, CDS1, CHK2, RAD53

Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978). Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-terminus). Interacts with SIRT1.

2XM8
CO-CRYSTAL STRUCTURE OF A SMALL MOLECULE INHIBITOR BOUND TO THE KINASE DOMAIN OF CHK2
RCSB/PDB
Inspect Structure
See all 3D Structures for CHEK2

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: CHEK2 is active in the following subcellular-locations: nucleoplasm, nucleus, pml body.
GO terms: CHEK2 is active in the following subcellular-locations: cytoplasm, Golgi apparatus, nucleoplasm, nucleus, PML body.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project CHEK2 has gain in 0 cell-lines, loss in 2 cell-lines and no signal in 1001 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: RPMI_8226, HCT_116, SK_MEL_28

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: PA-1, JHH-7, Pfeiffer

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HeLa-S3, MCF-7

(see details)

RNA Interference


CHEK2 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: BT549, H2228. (see details)

3D Structures


For CHEK2 there are:
38 structures (49 chains) solved
34 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


CHEK2 has been screened with 1577 compounds (2363 bioactivities), 162 compounds have bioactivities that show binding affinity of <= 500nM (182 bioactivities). (see details)