Ranasinghe, A. Dushani C.U.Lee, Daniel D.Schwarz, Margaret A.2023-04-102023-04-102020-12Ranasinghe 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.2020.158789https://hdl.handle.net/1805/32308Phosphorylation 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-USPublisher PolicyPulmonary arterial hypertensionBioactive lipidSphingosine kinase 1Endothelial monocyte activating polypeptide IIArticle