“…As another approach, we also overexpressed and purified the two versions of the complex in mammalian cells (Expi293F) and similarly analyzed PIKfyve phosphosites, with similar results (S48 and S2053 are differentially phosphorylated). These results strongly support the idea that, in addition to acting as PI(3,5)P 2 phosphatase, Fig4 is a serine phosphatase that regulates PIKfyve lipid kinase activity, explaining why an active form of Fig4 is required for normal levels of PI(3,5)P 2 in vivo (Duex et al, 2006a(Duex et al, , 2006bStrunk et al, 2020). PTEN, the phosphatase that dephosphorylates PI(3,4,5)P 3 during phosphatidylinositol 3-kinase (PI3K)/Akt signaling, also is active on protein substrates (Myers et al, 1997), setting a precedent for phosphatases with dual specificity on lipids and proteins.…”