PMID:22311981

Citation	Canals, D, Roddy, P and Hannun, YA (2012) Protein phosphatase 1α mediates ceramide-induced ERM protein dephosphorylation: a novel mechanism independent of phosphatidylinositol 4, 5-biphosphate (PIP2) and myosin/ERM phosphatase. J. Biol. Chem. 287:10145-55
Abstract	ERM (ezrin, radixin, and moesin) proteins are cytoskeletal interacting proteins that bind cortical actin, the plasma membrane, and membrane proteins, which are found in specialized plasma membrane structures such as microvilli and filopodia. ERM proteins are regulated by phosphatidylinositol 4, 5-biphosphate (PIP(2)) and by phosphorylation of a C-terminal threonine, and its inactivation involves PIP(2) hydrolysis and/or myosin phosphatase (MP). Recently, we demonstrated that ERM proteins are also subject to counter regulation by the bioactive sphingolipids ceramide and sphingosine 1-phosphate. Plasma membrane ceramide induces ERM dephosphorylation whereas sphingosine 1-phosphate induces their phosphorylation. In this work, we pursue the mechanisms by which ceramide regulates dephosphorylation. We found that this dephosphorylation was independent of hydrolysis and localization of PIP(2) and MP. However, the results show that ERM dephosphorylation was blocked by treatment with protein phosphatase 1 (PP1) pharmacological inhibitors and specifically by siRNA to PP1α, whereas okadaic acid, a PP2A inhibitor, failed. Moreover, a catalytic inactive mutant of PP1α acted as dominant negative of the endogenous PP1α. Additional results showed that the ceramide mechanism of PP1α activation is largely independent of PIP(2) hydrolysis and MP. Taken together, these results demonstrate a novel, acute mechanism of ERM regulation dependent on PP1α and plasma membrane ceramide.
Links	PubMed PMC3323024 Online version:10.1074/jbc.M111.306456
Keywords	Ceramides/genetics; Ceramides/metabolism; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Enzyme Inhibitors/pharmacology; HeLa Cells; Humans; Lysophospholipids/genetics; Lysophospholipids/metabolism; Mutation; Okadaic Acid/pharmacology; Phosphatidylinositol 4,5-Diphosphate/genetics; Phosphatidylinositol 4,5-Diphosphate/metabolism; Phosphorylation/drug effects; Phosphorylation/genetics; Protein Phosphatase 1/antagonists & inhibitors; Protein Phosphatase 1/genetics; Protein Phosphatase 1/metabolism; Protein Phosphatase 2/antagonists & inhibitors; Protein Phosphatase 2/genetics; Protein Phosphatase 2/metabolism; Sphingosine/analogs & derivatives; Sphingosine/genetics; Sphingosine/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PP1A	involved_in	GO:0006470: protein dephosphorylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PP1A	involved_in	GO:0016311: dephosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PP1A		GO:0016311: dephosphorylation	ECO:0000314:		P		Figure 8	complete CACAO 3738
HUMAN:PP1A		GO:0006470: protein dephosphorylation	ECO:0000315:		P		Figure 5: Knockdown of PP1 and PP2A isoforms in ERM dephosphorylation.	complete CACAO 5317

References

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