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MEK and ERK Activation in Ras-Disabled RBL-2H3 Mast Cells and Novel Roles for Geranylgeranylated and Farnesylated Proteins in FcRI-Mediated Signaling

Timothy E. Graham^*, Janet R. Pfeiffer^*, Rebecca J. Lee^2,*, Donna F. Kusewitt, A. Marina Martinez^*, Terry Foutz^*, Bridget S. Wilson^* and Janet M. Oliver^3,*

Departments of ^* Pathology and Cell Biology and Physiology and Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131

Cross-linking the high affinity IgE receptor FcRI of basophils and mast cells activates receptor-associated protein-tyrosine kinases and stimulates a signaling cascade leading to secretion, ruffling, spreading, and cytokine production. Previous evidence that the pan-prenylation inhibitor lovastatin blocks Ag-stimulated Ca²⁺ influx, secretion, and membrane/cytoskeletal responses implicated isoprenylated proteins in the FcRI-coupled signaling cascade but could not distinguish between contributions of C₁₅ (farnesylated) and C₂₀ (geranylgeranylated) species. Here we establish concentrations of lovastatin and the farnesyl-specific inhibitor BZA-5B that inhibit the farnesylation and Ag-induced activation of Ras species in RBL-2H3 cells (H-Ras, K-RasA, and K-RasB). These inhibitors have little effect on tyrosine kinase activation, which initiates FcRI signaling. Although Ras is disabled, only lovastatin substantially blocks Raf-1 activation, and neither inhibitor affects mitogen-activated protein kinase kinase/extracellular signal regulated kinase kinase (MEK) or ERK1/ERK2 activation. Thus, the pathway to FcRI-mediated MEK/ERK and ERK activation can apparently bypass Ras and Raf-1. Predictably, only lovastatin inhibits Ag-induced ruffling, spreading, and secretion, previously linked to geranylgeranylated Rho and Rab family members. Additionally, only lovastatin inhibits phospholipase C-mediated inositol (1,4,5) trisphosphate production, sustained Ca²⁺ influx, and Ca²⁺-dependent IL-4 production, suggesting novel roles for geranylgeranylated (lovastatin-sensitive, BZA-5B-insensitive) proteins in FcRI signal propagation. Remarkably, BZA-5B concentrations too low to inactivate Ras reduce the lag time to Ag-induced Ca²⁺ stores release and enhance secretion. These results link a non-Ras farnesylated protein(s) to the negative regulation of Ca²⁺ release from intracellular stores and secretion. We identified no clear role for Ras in FcRI-coupled signaling but suggest its involvement in mast cell growth regulation based on the inhibition of cell proliferation by both BZA-5B and lovastatin.

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