Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis.
Bottom Line: Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis.The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720.Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1(-/-) MEFs.
Affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.Show MeSH
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Mentions: To uncover the structural details of I2PP2A/SET-ceramide binding, molecular modelling/simulations were performed using the crystal structure of I2PP2A/SET (Muto et al, 2007) and C18-ceramide as a probe (Fig 1A). Our previous study showed that a single mutation with K209D conversion significantly inhibited the binding of I2PP2A/SET to ceramide both in vitro and in A549 cells (Mukhopadhyay et al, 2009). Accordingly, one of the prominent docking sites of I2PP2A/SET for ceramide binding included the K209 residue (Fig 1A and B, and Supporting Information Fig S1), which interacts with the primary hydroxyl group of ceramide possibly via charge attraction (Fig 1B, and Supporting Information Fig S1). The model also suggested that the K209 directly interacts with the Y122 residue via a hydrophobic–ionic (cation/π-arene) interaction (Fig 1B), possibly playing a role as a gate for regulating the access of ceramide to the hydrophobic pocket.
Affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.