The unmasking of the lipid binding face of sphingosine kinase 1

Abstract

Sphingosine-1-phosphate (S1P) is a pro-inflammatory lipid and pro-survival signal generated primarily by phosphorylation of sphingosine via sphingosine kinase 1 (SK1). SK1 is a ~43 kDa enzyme with two domains and an active site within a cleft between the two domains (1). While the role of SK1 in generating S1P and activating downstream targets is fairly well studied, there has been a paucity of information on how SK1 interacts with lipid membranes/cell membranes where it presumably accesses its substrate, sphingosine. SK1 has been linked to several types of cancers (2) where SK1 was found to be overexpressed (3) and expression levels are linked with patient survival and prognosis as well as chemotherapeutic resistance (4). SK1 also has been shown to have a central role in neurotransmission and endocytosis where SK1 membrane binding and S1P generation were critical for proper endocytic vesicle formation from the plasma membrane (5).Studies more than a decade ago demonstrated SK1 translocation from the cytosol to the plasma membrane following cellular stimulation with PMA (6) where the membrane fraction containing SK1 has increased levels of phosphorylation of substrate (7). Plasma membrane anionic lipids including phosphatidic acid (PA) and phosphatidylserine (PS) have been shown to stimulate SK1 activity (8) and recruit SK1 to membranes (9). Recent studies investigating a hydrophobic patch exposed on the SK1 structure revealed an important role for hydrophobic residues in SK1 membrane recruitment and loss of function in neurotransmission for hydrophobic mutants of SK1 (5). However, mechanisms by which SK1 is recruited to the membrane surface to interact with anionic lipids necessary for SK1 activity have not been well explored.In this issue of J. Lipid Res., Pulkoski-Gross et al. examine the ability of SK1 to interact with anionic membranes based upon the SK1 structure (10). Despite the structure of SK1 being solved more than four years ago, there has been little mechanistic information on how SK1 accesses its substrate in the context of membranes. The important new study by by guest, on May 11, 2018 www.jlr.org Downloaded from