An intrinsic lipid-binding interface controls sphingosine kinase 1 function

Pulkoski-Gross, Michael J.; Jenkins, Meredith L.; Truman, Jean‐Philip; Salama, Mohamed; Clarke, Christopher J.; Burke, John E.; Hannun, Yusuf A.; Obeid, Lina M.

doi:10.1194/jlr.m081307

Cited by 29 publications

(37 citation statements)

References 62 publications

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“…Upon closer examination of the currently published SK1 structures, Adams et al proposed a mechanism by which SK1 can form dimers and interact with membranes using a single contiguous interface [78]. Our lab has recently identified a new electrostatic site on SK1 and has shown that it forms a single interface, along with the hydrophobic patch, to effectively interact with membranes [80]. sdf This single contiguous interface is critical for the function of SK1 in cells [80].…”

Section: Introductionmentioning

confidence: 99%

“…Our lab has recently identified a new electrostatic site on SK1 and has shown that it forms a single interface, along with the hydrophobic patch, to effectively interact with membranes [80]. sdf This single contiguous interface is critical for the function of SK1 in cells [80]. Together the work of Pulkoski-Gross et al [80], Shen et al [79], and Adams et al [78] provide insight into an intrinsic mechanism for SK1 interaction with membranes.…”

Section: Introductionmentioning

confidence: 99%

“…sdf This single contiguous interface is critical for the function of SK1 in cells [80]. Together the work of Pulkoski-Gross et al [80], Shen et al [79], and Adams et al [78] provide insight into an intrinsic mechanism for SK1 interaction with membranes.…”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms of regulation of sphingosine kinase 1

Pulkoski-Gross

Obeid

2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Within the last 3 decades, there has been intense study of bioactive sphingolipids and the enzymes which metabolize those lipids. One enzyme is the critical lipid kinase sphingosine kinase 1 (SK1), which produces the potent and pleiotropic signaling lipid, sphingosine 1-phosphate (S1P). SK1 and S1P have been implicated in a host of different diseases including cancer, chronic inflammation, and metabolic diseases. However, while there is ample knowledge about the importance of these molecules in the development and progression of disease there is a dearth of knowledge of the molecular mechanisms which regulate SK1 function. In this review, we will cover some of the more recent and exciting findings about the different ways SK1 function can be regulated, from transcriptional regulation to protein stability. Finally, we will delve into recent structural insights into SK1 and how they might relate to function at cell membranes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms of regulation of sphingosine kinase 1

Pulkoski-Gross

Obeid

2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…The SK1 Leu 194 residue, which was shown to be an important part of membrane binding activity of SK1 in the study by Pulkoski-Gross et al (10) as well as a previous study (5), is part of an -helix with several exposed hydrophobic residues (Leu 187 , Met 189 , and Leu 198 ) (See Fig. 1).…”

Section: Experiments With Hydrogen-deuterium Exchange Mass Spectrometmentioning

confidence: 99%

“…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.…”

Section: *Corresponding Author: Rstaheli@purdueedumentioning

confidence: 99%

The unmasking of the lipid binding face of sphingosine kinase 1

Stahelin

2018

Journal of Lipid Research

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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

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Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Jamal

Briolay

Mébarek

et al. 2019

Journal of Bone and Mineral Research

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Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1‐phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF‐α and IL‐17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro‐inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR‐induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3, but their contribution to S1P‐impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.

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An intrinsic lipid-binding interface controls sphingosine kinase 1 function

Cited by 29 publications

References 62 publications

Molecular mechanisms of regulation of sphingosine kinase 1

Molecular mechanisms of regulation of sphingosine kinase 1

The unmasking of the lipid binding face of sphingosine kinase 1

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

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