Mechanistic regulation of SPHK1 expression and translocation by EMAP II in pulmonary smooth muscle cells
Phosphorylation of sphingosine by sphingosine kinase 1 (SPHK1) produces the bioactive sphingolipid sphingosine-1-phosphate (S1P), a microvascular and immuno-modulator associated with vascular remodeling in pulmonary arterial hypertension (PAH). The low intracellular concentration of S1P is under tig...
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Veröffentlicht in: | Biochimica et biophysica acta. Molecular and cell biology of lipids 2020-12, Vol.1865 (12), p.158789-158789, Article 158789 |
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Sprache: | eng |
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Zusammenfassung: | Phosphorylation of sphingosine by sphingosine kinase 1 (SPHK1) produces the bioactive sphingolipid sphingosine-1-phosphate (S1P), a microvascular and immuno-modulator associated with vascular remodeling in pulmonary arterial hypertension (PAH). The low intracellular concentration of S1P is under tight spatial-temporal control. Molecular mechanisms that mediate S1P burden and S1P regulation of vascular remodeling are poorly understood. Similarities between two early response pro-inflammatory cytokine gene transcript activation profiles, S1P and Endothelial Monocyte Activating Polypeptide II (EMAP II), suggested a strategic link between their signaling pathways. We determined that EMAP II triggers a bimodal phosphorylation, transcriptional regulation and membrane translocation of SPHK1 through a common upstream process in both macrophages and pulmonary artery smooth muscle cells (PASMCs). EMAP II initiates a dual function of ERK1/2: phosphorylation of SPHK1 and regulation of the transcription factor EGR1 that induces expression of SPHK1. Activated ERK1/2 induces a bimodal phosphorylation of SPHK1 which reciprocally increases S1P levels. This identified common upstream signaling mechanism between a protein and a bioactive lipid initiates cell specific downstream signaling representing a multifactorial mechanism that contributes to inflammation and PASMC proliferation which are cardinal histopathological phenotypes of PAH.
•EMAP II triggers bimodal phosphorylation of sphingosine generating the bioactive sphingolipid S1P by catalyzing SPHK1.•SPHK1 transcriptional regulation and phosphorylation is EMAP II regulated.•Cellular response mediated by EMAP II modulation of sphingosine phosphorylation and SPHK1 translocation.•Cell specific activation of S1P mediated pro-inflammatory and proliferative smooth muscle cellular responses could impact PAH. |
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ISSN: | 1388-1981 1879-2618 |
DOI: | 10.1016/j.bbalip.2020.158789 |