Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A.

ABSTRACT: Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear le

SUBMITTER: Jayashankar V 

PROVIDER: S-EPMC12361511 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature