Neuronal calcium sensor-1 and phosphatidylinositol 4-kinase β stimulate extracellular signal-regulated kinase 1/2 signaling by accelerating recycling through the endocytic recycling compartment

Yaara Kapp-Barnea, Lihi Ninio-Many, Koret Hirschberg, Mitsunori Fukuda, Andreas Jeromin, Ronit Sagi-Eisenberg

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

We demonstrate that recycling through the endocytic recycling compartment (ERC) is an essential step in FcεRI-induced activation of extracellular signal-regulated kinase (ERK)1/2. We show that ERK1/2 acquires perinuclear localization and colocalizes with Rab 11 and internalized transferrin in FcεRI-activated cells. Moreover, a close correlation exists between the amount of ERC-localized ERK1/2 and the amount of phospho-ERK1/2 that resides in the nucleus. We further show that by activating phosphatidylinositol 4-kinase β (PI4Kβ) and increasing the cellular level of phosphatidylinositol(4) phosphate, neuronal calcium sensor-1 (NCS-1), a calmodulin-related protein, stimulates recycling and thereby enhances FcεRI-triggered activation and nuclear translocation of ERK1/2. Conversely, NCS-1 short hairpin RNA, a kinase dead (KD) mutant of PI4Kβ (KD-PI4Kβ), the pleckstrin homology (PH) domain of FAPP1 as well as RNA interference of synaptotagmin IX or monensin, which inhibit export from the ERC, abrogate FcεRI-induced activation of ERK1/2. Consistently, NCS-1 also enhances, whereas both KD-PI4Kβ and FAPP1-PH domain inhibit, FcεRI-induced release of arachidonic acid/metabolites, a downstream target of ERK1/2 in mast cells. Together, our results demonstrate a novel role for NCS-1 and PI4Kβ in regulating ERK1/2 signaling and inflammatory reactions in mast cells. Our results further identify the ERC as a crucial determinant in controlling ERK1/2 signaling.

Original languageEnglish
Pages (from-to)4130-4141
Number of pages12
JournalMolecular biology of the cell
Volume17
Issue number9
DOIs
Publication statusPublished - 2006 Sep

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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