Chk1 Recombinant Rabbit Monoclonal Antibody [ST57-09]

Function

Cell cycle events are regulated by the sequential activation and deactivation of cyclin dependent kinases (Cdks) and by proteolysis of cyclins. Chk1 and Chk2 are involved in these processes as regulators of Cdks. Chk1 and Chk2 both function as essential components in the G2 DNA damage checkpoint by phosphorylating Cdc25C in response to DNA damage. Phosphorylation inhibits Cdc25C activity, thereby blocking mitosis. Cdc25A, Cdc25B and Cdc25C protein tyrosine phosphatases function as mitotic activators by dephosphorylating Cdc2 p34 on regulatory tyrosine residues. It has also been shown that Chk1 can phosphorylate Wee1 in vitro, providing evidence that the hyperphosphorylated form of Wee1, seen in cells delayed by Chk1 overexpression, is due to phosphorylation by Chk1.

Background References

1. Okita N et al. CHK1 cleavage in programmed cell death is intricately regulated by both caspase and non-caspase family proteases. Biochim Biophys Acta 1830:2204-13 (2013).

2. Gray JE et al. A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors. Clin Cancer Res 20:1644-55 (2014).

Sequence Similarity

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.

Tissue Specificity

Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.

Post-translational Modification

Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.; Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication.

Subcellular Location

Cytoplasm, Nucleus.

UNIPROT

SwissProt: O14757 Human

Synonyms