Cancer

Lung cancer (LC); Lung cancer (LC), Somatic

COT appears to be an oncoprotein (OP), although it is not subject to a higher rate of mutation in human cancers than most proteins. The active form of the protein kinase normally acts to promote tumour cell proliferation.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= -68, p<0.032); Brain glioblastomas (%CFC= -62, p<0.071); Breast epithelial carcinomas (%CFC= -70, p<0.064); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +482, p<0.029); Ovary adenocarcinomas (%CFC= -69, p<0.002); Prostate cancer - primary (%CFC= +281, p<0.0001); and Uterine leiomyomas from fibroids (%CFC= -48, p<0.065). The COSMIC website notes an up-regulated expression score for COT in diverse human cancers of 349, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. Catalytic activity of COT can be abrogated with K167R or D270A mutations. IL-1 stimulated activity is decreased with S62A. This mutation can also inhibit IL-1 stimulated phosphorylation of T290 along with MEK phosphorylation when associated with A400. Full inhibition of IL-1 induced MEK phosphorylation and partial inhibition of autophosphorylation can occur with a T290A mutation. Partial inhibition of MEK phosphorylation and autophosphorylation can be achieved with a T290A or T290E mutation. Partial impairment of MEK phosphorylation induced by IL-1 has been observed with a S400A mutation. When COT is associated with A62, a complete loss of T290 and MEK phosphorylation occurs with a S400A mutation.

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 25491 diverse cancer specimens. This rate is only -8 % lower and is very similar to the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.43 % in 602 endometrium cancers tested; 0.37 % in 1093 large intestine cancers tested; 0.17 % in 1226 kidney cancers tested.

Most frequent mutations with the number of reports indicated in brackets: P296S (9). These are located in the kinase catalytic domain.

Only 1 deletion and 2 insertions and no complex mutations are noted on the COSMIC website.