MAP kinases are inactivated by dual-specificity protein phosphatases that differ in their substrate specificity, tissue distribution, inducibility by extracellular stimuli, and cellular localization. DUSPs, also known as MAPK phosphatases, specifically dephosphorylate both threonine and tyrosine residues in MAPK P-loops and have been shown to play important roles in regulating the function of the MAPK family. At least 13 members of the family display unique substrate specificities for various MAP kinases. MAPK phosphatases typically contain an amino-terminal rhodanese-fold responsible for DUSP docking to MAPK family members and a carboxy-terminal catalytic domain. These phosphatases can play important roles in development, immune system function, stress responses, and metabolic homeostasis. In addition, research studies have implicated DUSPs in the development of cancer and the response of cancer cells to chemotherapy.DUSP9 has been implicated in cancer, although expression level and effect on downstream signaling pathways are varied. In colorectal carcinoma, for example, it has been shown that the levels of DUSP9 are reduced in cancerous tissue compared to normal adjacent tissue, and in clear cell renal carcinoma cell line and xenograft experiments decreased DUSP9 was also observed, suggesting that it may be a tumor suppressor in some cell types. In contrast, in some difficult to treat triple negative breast cancers, experiments suggest DUSP9 activity and expression is abnormally elevated, particularly in cancer-like stem cells in these tumors.DUSP9 has also been shown to be a key suppressor of high-fat diet-induced hepatic steatosis and inflammatory responses in liver. Since no drugs have yet to be approved for NAFLD and NASH, therapeutics to increase expression of DUSP9 in liver are of interest.
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