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Vol. 17, Issue 9, 4130-4141, September 2006

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Neuronal Calcium Sensor-1 and Phosphatidylinositol 4-Kinase 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^||, and Ronit Sagi-Eisenberg^*

Departments of *Cell and Developmental Biology and Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Department of Developmental Biology and Neurosciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan; and ^||Center for Learning and Memory, University of Texas at Austin, Austin, TX 78712

Submitted November 4, 2005; Revised June 15, 2006; Accepted June 30, 2006
Monitoring Editor: Jean Gruenberg

We demonstrate that recycling through the endocytic recycling compartment (ERC) is an essential step in FcRI-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 FcRI-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 (PI4K) and increasing the cellular level of phosphatidylinositol(4) phosphate, neuronal calcium sensor-1 (NCS-1), a calmodulin-related protein, stimulates recycling and thereby enhances FcRI-triggered activation and nuclear translocation of ERK1/2. Conversely, NCS-1 short hairpin RNA, a kinase dead (KD) mutant of PI4K (KD-PI4K), the pleckstrin homology (PH) domain of FAPP1 as well as RNA interference of synaptotagmin IX or monensin, which inhibit export from the ERC, abrogate FcRI-induced activation of ERK1/2. Consistently, NCS-1 also enhances, whereas both KD-PI4K and FAPP1-PH domain inhibit, FcRI-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 PI4K 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.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05.11-1014) on July 12, 2006.

These authors contributed equally to this work.

Address correspondence to: Ronit Sagi-Eisenberg (histol3{at}post.tau.ac.il)

Abbreviations used: DNP, dinitrophenyl; ERC, endocytic recycling compartment; NCS-1, neuronal calcium sensor-1; PI4K, phosphatidylinositol 4-kinase ; Tfn, transferrin

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