Neuronal calcium sensor-1 and phosphatidylinositol 4-kinase beta stimulate extracellular signal-regulated kinase 1/2 signaling by accelerating recycling through the endocytic recycling compartment.
We demonstrate that recycling through the endocytic recycling compartment (ERC) is an essential step in Fc epsilonRI-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 Fc epsilonRI-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 beta (PI4Kbeta) and increasing the cellular level of phosphatidylinositol(4) phosphate, neuronal calcium sensor-1 (NCS-1), a calmodulin-related protein, stimulates recycling and thereby enhances Fc epsilonRI-triggered activation and nuclear translocation of ERK1/2. Conversely, NCS-1 short hairpin RNA, a kinase dead (KD) mutant of PI4Kbeta (KD-PI4Kbeta), the pleckstrin homology (PH) domain of FAPP1 as well as RNA interference of synaptotagmin IX or monensin, which inhibit export from the ERC, abrogate Fc epsilonRI-induced activation of ERK1/2. Consistently, NCS-1 also enhances, whereas both KD-PI4Kbeta and FAPP1-PH domain inhibit, Fc epsilonRI-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 PI4Kbeta 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.
Kapp-Barnea
Yaara
Y
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Ninio-Many
Lihi
L
Hirschberg
Koret
K
Fukuda
Mitsunori
M
Jeromin
Andreas
A
Sagi-Eisenberg
Ronit
R
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D006801:Humans; D000090204:Mesothelin; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002135:Calcium-Binding Proteins; C502447:MS4A2 protein, human; C000715529:Msln protein, rat; D050505:Mutant Proteins; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D017455:Receptors, IgE; D014168:Transferrin; C101464:frequenin calcium sensor proteins; D016718:Arachidonic Acid; D019870:1-Phosphatidylinositol 4-Kinase; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000090204:Mesothelin