Cancer

Melanomas

ASK1 appears to be a tumour suppressor protein (TSP)The active form of the protein kinase normally acts to inhibit tumour cell proliferation. Mutations in the MAP3K5 gene have been observed in cancer patients, indicating a role for the protein in cancer pathology. For example, 24% of melanoma cell lines were found to contain mutations in the coding-regions of either MAP3K5 or the closely related kinase MAP3K9. Some of these mutations were found in the kinase catalytic domain, which were predicted to affect the catalytic activity of MAP3K5. In addition, loss of heterozygosity in MAP3K5 was observed in 85% of melanoma specimens, indicating that the previously observed mutations result in the loss-of-function in the protein. In vitro assays of MAP3K5 with an I780F substitution, the most commonly observed mutant form of the kinase, showed reduced phosphotransferase activity when compared to wild-type MAP3K5. It appears to be a tumour-suppressor protein with an important role in the prevention of cancer development.
 

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: Barrett's esophagus epithelial metaplasia (%CFC= +46, p<0.0007); Bladder carcinomas (%CFC= +95, p<0.0009); Cervical cancer stage 2B (%CFC= -64, p<0.081); Colon mucosal cell adenomas (%CFC= +53, p<0.0001); Oral squamous cell carcinomas (OSCC) (%CFC= +103, p<0.0001); Papillary thyroid carcinomas (PTC) (%CFC= +77, p<0.1); Pituitary adenomas (aldosterone-secreting) (%CFC= -57, p<0.0002); Skin melanomas - malignant (%CFC= -66, p<0.002); Skin squamous cell carcinomas (%CFC= +92, p<0.01); T-cell prolymphocytic leukemia (%CFC= -50, p<0.005); Uterine leiomyomas from fibroids (%CFC= -55, p<0.0002); and Vulvar intraepithelial neoplasia (%CFC= +75, p<0.0001). The COSMIC website notes an up-regulated expression score for ASK1 in diverse human cancers of 287, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 40 for this protein kinase in human cancers was 0.7-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25403 diverse cancer specimens. This rate is only -14 % lower than 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: 0.38 % in 805 skin cancers tested; 0.27 % in 602 endometrium cancers tested; 0.26 % in 1093 large intestine cancers tested; 0.15 % in 500 urinary tract cancers tested; 0.1 % in 1942 lung cancers tested; 0.06 % in 1466 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S53S (11).

Only 4 deletions, 3 insertions, and 2 complex mutations are noted on the COSMIC website.