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Cell Signal. 2018 Dec;52:147-154. doi: 10.1016/j.cellsig.2018.09.005. Epub 2018 Sep 10.

Ligand-mediated dephosphorylation signaling for MAP kinase.

Author information

1
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007, USA.
2
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007, USA. Electronic address: ys82@georgetown.edu.

Abstract

Extracellular signal-regulated kinase (ERK), also known as classical mitogen-activated protein kinase, plays critical roles in cell regulation. ERK is activated through phosphorylation by a cascade of protein kinases including MEK. Various ligands activate the MEK/ERK pathway through receptor-dependent cell signaling. In cultured cells, many ligands such as growth factors, hormones, cytokines and vasoactive peptides elicit transient activation of MEK/ERK, often peaking at ~10 min after the cell treatment. Here, we describe a novel biological event, in which ligand-mediated cell signaling results in the dephosphorylation of MEK/ERK. Neuromedin N and neurotensin, peptides derived from the same precursor polypeptide, elicit cell signaling through the neurotensin receptors. In cultured human pulmonary artery smooth muscle cells (PASMCs), but not in human pulmonary artery endothelial cells (PAECs), we found that both neuromedin N and neurotensin promoted the dephosphorylation of ERK and MEK. Human PASMCs were found to express neurotensin receptor (NTR)-1, -2 and -3, while human PAECs only express NTR3. Neuromedin N-mediated dephosphorylation was suppressed by small chemical inhibitors of protein phosphatase 1/2A and peptidyl-prolyl isomerase. Transmission electron microscopy showed the formation of endocytic vesicles in response to neuromedin N treatment, and dephosphorylation did not occur when sorting nexin 9, a critical regulator of the endocytic vesicle formation, was knocked down. We conclude that neuromedin N and neurotensin elicit a unique dephosphorylation signaling in the MEK/ERK pathway that is regulated by endocytosis. Considering the pathophysiological importance of the MEK/ERK pathway, this discovery of the dephosphorylation mechanism should advance the field of cell signaling.

KEYWORDS:

Dephosphorylation; Endocytosis; MAP kinase; Neuromedin N; Neurotensin

PMID:
30213686
DOI:
10.1016/j.cellsig.2018.09.005
[Indexed for MEDLINE]

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