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Dissecting G.sub.q/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1
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Dissecting G.sub.q/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1
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Journal Article
Dissecting G.sub.q/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1
2020
Overview
Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphKl), thereby enabling inside-out signaling of sphingosine-l-phosphate. We have shown before that [G.sub.q]-coupled receptors and constitutively active [G[alpha].sub.q/11] specifically induced a rapid and long-lasting SphKl translocation, independently of canonical [G.sub.q]/phospholipase C (PLC) signaling. Here, we further characterized [G.sub.q/11] regulation of SphKl. SphKl translocation by the [M.sub.3] receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLC[[beta].sub.3], but accelerated by wild-type PLC[[beta].sub.3] and the PLC[delta] PH domain. Both wild-type SphKl and catalytically inactive SphKl-G82D reduced [M.sub.3] receptor-stimulated inositol phosphate production, suggesting competition at [G[alpha].sub.q]. Embryonic fibroblasts from [G[alpha].sub.q/11] double-deficient mice were used to show that amino acids W263 and T257 of [G[alpha].sub.q], which interact directly with PLC[[beta].sub.3] and p63RhoGEF, were important for bradykinin [B.sub.2] receptor-induced SphKl translocation. Finally, an AIXXPL motif was identified in vertebrate SphKl (positions 100-105 in human SphKla), which resembles the [G[alpha].sub.q] binding motif, ALXXPI, in PLC[beta] and p63RhoGEF. After [M.sub.3] receptor stimulation, SphKl-AlOOE-IlOlE and SphKl-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLC[beta]/PLC[delta](PH) expression are important for regulation of SphKl by [G.sub.q/11].
Publisher
MDPI AG
Subject
