Human Dual Specificity Phosphatase 18 Functional Studies And Act-17a / T Polymorphism And Alzheimer's Disease Susceptibility Meta Analysis

Dual-specificity protein phosphatases (DSPs), characterized by the ability to dephosphorylate both phospho-tyrosyl and phospho-seryl/threonyl residues, are a new family of protein tyrosine phosphatases (PTPs). DUSP18 (Dual-specificity protein phosphatase 18) is a atypical DUSPs, and is widely expressed in almost all cells and tissues. It subcellular localized in both cytoplasm and nucleus and don't change after stimulation.Experiments revealed that DUSP18 could interact with JNK1a1,JNK1b1 and JNK3al and dephosphorylat them. DUSP18's expression which had a 3-fold increase in 15 min after stimulation with 10% serum after 18 hour starvation and JNK had the similar pattern is under the control by phosphorylation of JNK. Increased expression of JNK could not up regulate the expression of DUSP18 in contrast to that SP600125, as a JNK specific inhibitor, could retract the up regulated expression, all these results demonstrate that DUSP18 acts as a feedback of JNK pathway.The same stimulation by serum with DUSP18 RNAi increased cell apoptosis while repressed with exogenous excessive expression of DUSP18. It's of interest that exogenous excessive expression of DUSP18 could cause an increase of apoptosis. Changing of DUSP18's expression shows no effect to cancer cells'growth.In order to identify other pathway that DUSP18 take part in the control of, we used a JAK/STAT pathway Phospho Antibody Array and cells transfected with His-DUSP18, we found that phosphorylation level of several proteins in the pathway changed. On top of the array data, we used an Apoptosis Phospho Antibody Array with major pathways related to apoptosis for further research. Our results reveal that DUSP18 takes part in several pathway such as PI3K/Akt,NF-κB and TGF-β/Smad.Furthermore, our experiments in vitro and in vivo reveal that DUSP18 could interact with LGAL3,PRDX1,TFG and IMPDH2.In summary, our series functioned study experiments especially about the role of DUSP18 in apoptosis reveal that DUSP18 is an important feedback regulatory factor of SAPK/JNK pathway in vivo and take part in manifold key signaling pathways associated with apoptosis, and may manipulate other critical cell physiological processes.