Protein phosphatase 2Cε is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes

Satoko Saito, Hiroyuki Matsui, Miyuki Kawano, Keigo Kumagai, Nario Tomishige, Kentaro Hanada, Seishi Echigo, Shinri Tamura, Takayasu Kobayashi

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

Abstract

Protein phosphatase 2C∈ (PP2C∈), a mammalian PP2C family member, is expressed in various tissues and is implicated in the negative regulation of stress-activated protein kinase pathways. We show that PP2C∈ is an endoplasmic reticulum (ER) transmembrane protein with a transmembrane domain at the amino terminus and the catalytic domain facing the cytoplasm. Yeast two-hybrid screening of a human brain library using PP2C∈ as bait resulted in the isolation of a cDNA that encoded vesicle-associated membrane protein-associated protein A (VAPA). VAPA is an ER resident integral membrane protein involved in recruiting lipid-binding proteins such as the ceramide transport protein CERT to the ER membrane. Expression of PP2C∈ resulted in dephosphorylation of CERT in a VAPA expression-dependent manner, which was accompanied by redistribution of CERT from the cytoplasm to the Golgi apparatus. The expression of PP2C∈ also enhanced the association between CERT and VAPA. In addition, knockdown of PP2C∈ expression by short interference RNA attenuated the interaction between CERT and VAPA and the sphingomyelin synthesis. These results suggest that CERT is a physiological substrate of PP2C∈ and that dephosphorylation of CERT by PP2C∈ may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.

Original languageEnglish
Pages (from-to)6584-6593
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number10
DOIs
Publication statusPublished - 2008 Mar 7

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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