Mechanistic regulation of SPHK1 expression and translocation by EMAP II in pulmonary smooth muscle cells
dc.contributor.author | Ranasinghe, A. Dushani C.U. | |
dc.contributor.author | Lee, Daniel D. | |
dc.contributor.author | Schwarz, Margaret A. | |
dc.contributor.department | Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2023-04-10T13:22:56Z | |
dc.date.available | 2023-04-10T13:22:56Z | |
dc.date.issued | 2020-12 | |
dc.description.abstract | 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. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Ranasinghe ADCU, Lee DD, Schwarz MA. Mechanistic regulation of SPHK1 expression and translocation by EMAP II in pulmonary smooth muscle cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(12):158789. doi:10.1016/j.bbalip.2020.158789 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/32308 | |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.isversionof | 10.1016/j.bbalip.2020.158789 | en_US |
dc.relation.journal | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Pulmonary arterial hypertension | en_US |
dc.subject | Bioactive lipid | en_US |
dc.subject | Sphingosine kinase 1 | en_US |
dc.subject | Endothelial monocyte activating polypeptide II | en_US |
dc.title | Mechanistic regulation of SPHK1 expression and translocation by EMAP II in pulmonary smooth muscle cells | en_US |
dc.type | Article | en_US |