Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1

Martha M Monick; Linda S Powers; Thomas J Gross; Dawn M Flaherty; Christopher W Barrett; Gary W Hunninghake

doi:10.4049/jimmunol.177.3.1636

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Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1

Journal article

Peer reviewed

Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1

Martha M Monick, Linda S Powers, Thomas J Gross, Dawn M Flaherty, Christopher W Barrett and Gary W Hunninghake

The Journal of immunology (1950), Vol.177(3), pp.1636-1645

08/01/2006

DOI: 10.4049/jimmunol.177.3.1636

PMID: 16849472

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Abstract

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.

Phosphorylation

Protein Biosynthesis

JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors

Humans

Phosphoprotein Phosphatases - metabolism

Cells, Cultured

Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors

JNK Mitogen-Activated Protein Kinases - metabolism

Protein Tyrosine Phosphatases - metabolism

Phosphoprotein Phosphatases - antagonists & inhibitors

Cell Survival - immunology

Enzyme Activation - immunology

Macrophages, Alveolar - enzymology

Protein Tyrosine Phosphatases - antagonists & inhibitors

Signal Transduction - immunology

Up-Regulation - immunology

Down-Regulation - immunology

JNK Mitogen-Activated Protein Kinases - physiology

Eukaryotic Initiation Factor-2 - metabolism

Macrophages, Alveolar - cytology

Mitogen-Activated Protein Kinase Phosphatases

Dual-Specificity Phosphatases

Extracellular Signal-Regulated MAP Kinases - physiology

Protein Phosphatase 1

Details

Title: Subtitle: Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1
Creators: Martha M Monick - University of Iowa Carver College of Medicine, Veterans Administration Medical Center, Iowa City, IA 52242, USA. martha-monick@uiowa.edu
Linda S Powers
Thomas J Gross
Dawn M Flaherty
Christopher W Barrett
Gary W Hunninghake
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.177(3), pp.1636-1645
DOI: 10.4049/jimmunol.177.3.1636
PMID: 16849472
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: HL079901-01A1 / NHLBI NIH HHS HL-60316 / NHLBI NIH HHS HL-077431 / NHLBI NIH HHS RR00059 / NCRR NIH HHS
Language: English
Date published: 08/01/2006
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984094874202771

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