Sec6 modulates PP2A phosphatase activity through alteration of the binding affinity of PP2A in A and C subunits

Abstract Dephosphorylation of the activated the regulator of a-fetoprotein (Raf)-MAP/ERK kinase (MEK)-the extracellular signal-regulated protein kinase (ERK)-p90 ribosomal protein 6 kinase (RSK) cascade plays an essential role in regulating the magnitude and duration of kinase activation and the nature of the physiological response. The protein phosphatase 2A (PP2A), which is one of the major serine/threonine phosphatases, plays a pivotal role in various signaling pathways including cell cycle, metabolism, migration, and cell death. The impairment of PP2A activity is associated with various diseases including neurodegenerative disorders, autoimmune diseases, type II diabetes, and tumors. However, little is known about how cells control the assembly of PP2A subunits and stabilize PP2A phosphatase activity. In the present study, we demonstrate that Sec6 regulates PP2A phosphatase activity by modulating the binding affinity of the A and C subunits of PP2A, thereby modulating the phosphorylation of p90RSK at Thr359 and Ser380, glycogen synthase kinase 3b (GSK3b) at Ser9, and the expression of zinc finger E-box binding homeobox 1 (ZEB1), vimentin, and zonula occludens 3 (ZO-3).