Active ERK Contributes to Protein Translation by Preventing JNK-Dependent Inhibition of Protein Phosphatase 1

• Published in: Journal of Immunology Vol. 177; no. 3; pp. 1636 - 1645
• Main Authors: Monick, Martha M, Powers, Linda S, Gross, Thomas J, Flaherty, Dawn M, Barrett, Christopher W, Hunninghake, Gary W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.08.2006
• Subjects: Cell Survival - immunology; Cells, Cultured; Down-Regulation - immunology; Dual-Specificity Phosphatases; Enzyme Activation - immunology; Eukaryotic Initiation Factor-2 - metabolism; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; JNK Mitogen-Activated Protein Kinases - physiology; Macrophages, Alveolar - cytology; Macrophages, Alveolar - enzymology; Mitogen-Activated Protein Kinase Phosphatases; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Protein Biosynthesis; Protein Phosphatase 1; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Signal Transduction - immunology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.3.1636

Human alveolar macrophages, central to immune responses in the lung, are unique in that they have an extended life span in contrast to precursor monocytes. We have shown previously that the ERK MAPK (ERK) pathway is constitutively active in human alveolar macrophages and contributes to the prolonged survival of these cells. We hypothesized that ERK maintains survival, in part, by positively regulating protein translation. In support of this hypothesis, we have found novel links among ERK, JNK, protein phosphatase 1 (PP1), and the eukaryotic initiation factor (eIF) 2alpha. eIF2alpha is active when hypophosphorylated and is essential for initiation of protein translation (delivery of initiator tRNA charged with methionine to the ribosome). Using [(35)S]methionine labeling, we found that ERK inhibition significantly decreased protein translation rates in alveolar macrophages. Decreased protein translation resulted from phosphorylation (and inactivation) of eIF2alpha. We found that ERK inhibition increased JNK activity. JNK in turn inactivated (via phosphorylation) PP1, the phosphatase responsible for maintaining the hypophosphorylated state of eIF2alpha. As a composite, our data demonstrate that in human alveolar macrophages, constitutive ERK activity positively regulates protein translation via the following novel pathway: active ERK inhibits JNK, leading to activation of PP1alpha, eIF2alpha dephosphorylation, and translation initiation. This new role for ERK in alveolar macrophage homeostasis may help to explain the survival characteristic of these cells within their unique high oxygen and stress microenvironment.