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https://www.selleckchem.com/products/FK-506-(Tacrolimus).html We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity. Moreover, PPM1B-mediated dephosphorylation of DYRK1A reduced tau phosphorylation at Thr212, leading to inhibition of toxic tau oligomerization and aggregation. In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity. This finding also suggests that PPM1B reduces the toxic formation of phospho-tau protein via DYRK1A modulation, possibly providing a novel cellular protective mechanism to regulate toxic tau-mediated neuropathology in AD of DS.The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylation are implicated in cancer and Alzheimer disease (AD). Here, we tested the hypothesis that the methylation state of PP2A catalytic subunit, which influences PP2A subunit composition and substrate specificity, can affect Fyn regulation and function. Using N2a neuroblastoma cell models, we first show that methylated PP2A holoenzymes containing the Bα subunit co-immunoprecipitate and co-purify with Fyn in membrane rafts. PP2A methylation status regulates Fyn distribution and Fyn-dependent neuritogenesis, likely in part by affecting actin dynamics. A methylation incompetent PP2A mutant fails to interact with Fyn. It perturbs the normal partitioning of Fyn and amyloid precursor protein (APP) in membrane microdomains, which governs Fyn function and APP processing. This correlates with enhanced amyloidogenic cleavage of APP, a hallmark of AD pathogenesis. Conversely, enhanced PP2A methylation promotes the nonamyloidogenic cleavage of APP in a Fyn-dependent manner. Disturbances in one-carbon metabolic pathways that control cellular methylation are associated with AD and cancer. Notably, they

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