Cancer, inflammatory, and immune disorders

Primary sclerosing cholangitis (PSC); Sclerosing cholangitis; T-cell immunodeficiency, Recurrent infections, autoimmunity, and cardiac malformations

Primary Sclerosing Cholangitis (PSC) is a gastrointestinal disease where the bile ducts are inflamed and partially obstructed leading to accumulation of bile in the liver. PSC will lead to liver cirrhosis and failure over time. Sclerosing Cholangitis is related to Primary Sclerosing Cholangitis and can affect the liver, colon, and T cells. The rare immune disorder, T-Cell Immunodeficiency, Recurrent Infections, Autoimmunity, and Cardiac Malformations, which has also been called Combined Immunodeficiency due to stk4 deficiency is characterized by recurring viral, bacterial, or fungal infections, loss of naive T cells, abscesses, warts, autoimmunity, and cardiac dysfunctions. MST1 kinase phosphotransferase activity can be lost with either a K59R or a T183A mutation. Proteolytic cleavage of MST1 during apoptosis can be reduced with the D326N and D349N mutations.
 

Pancreatic cancer; Merkel cell carcinomas

MST1 is linked to pancreatic cancer, which is a rare cancer that does not have characteristic symptoms but is related to the integrated breast cancer and pancreatic cancer pathways.
 

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: Brain oligodendrogliomas (%CFC= -54, p<0.038); Breast epithelial carcinomas (%CFC= +98, p<0.082); and Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +1050, p<0.0006). The COSMIC website notes an up-regulated expression score for MST1 in diverse human cancers of 676, which is 1.5-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 49 for this protein kinase in human cancers was 0.8-fold of 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. MST1 phosphotransferase activity can be lost with either a K59R or a T183A mutation. Proteolytic cleavage of MST1 during apoptosis can be reduced with the D326N and D349N mutations. Homodimerization and autophosphorylation can be lost with a L444P mutation.

Percent mutation rates per 100 amino acids length in human cancers: 0.05 % in 25159 diverse cancer specimens. This rate is only -27 % 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: 0.34 % in 602 endometrium cancers tested; 0.28 % in 1093 large intestine cancers tested.

None > 6 in 19,967 cancer specimens

No deletions, insertions or complex mutations are noted on the COSMIC website.