Sphingosine kinase 2 and multiple myeloma

News on: Sphingosine kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress, by Wallington-Beddoe et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115

Selectivity and Specificity of Sphingosine 1-Phosphate Receptor Ligands: “Off-Targets” or Complex Pharmacology?

A recent perspective published in Frontiers of Pharmacology by Salomone and Waeber (2011) discussed the selectivity and specificity of sphingosine 1-phosphate (S1P) receptor ligands. This perspective surveyed the use of various S1P receptor ligands and attempted to reconcile a number of inconsistencies in the predicted biological outcomes: these were interpreted as “off-target” effects. Therefore the perspective cautioned against the use of these S1P receptor ligands. Here we highlight the complex pharmacology of S1P receptors, which along with “inside-out” signaling might provide an alternative explanation for “off-target” effects

Sphingosine 1-phosphate turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

S1P (sphingosine 1-phosphate) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC 2.7.1.91). It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC 4.1.2.27). Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery

Sphingosine 1-phosphate turnover in GtoPdb v.2023.1

S1P (sphingosine 1-phosphate) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC 2.7.1.91). It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC 4.1.2.27). Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery

Ceramide and sphingosine 1-phosphate in adipose dysfunction

The increased adipose tissue mass of obese individuals enhances the risk of metabolic syndrome, type 2 diabetes and cardiovascular diseases. During pathological expansion of adipose tissue, multiple molecular controls of lipid storage, adipocyte turn-over and endocrine secretion are perturbed and abnormal lipid metabolism results in a distinct lipid profile. There is a role for ceramides and sphingosine 1-phosphate (S1P) in inducing adipose dysfunction. For instance, the alteration of ceramide biosynthesis, through the de-regulation of key enzymes, results in aberrant formation of ceramides (e.g. C16:0 and C18:0) which block insulin signaling and promote adipose inflammation. Furthermore, S1P can induce defective adipose tissue phenotypes by promoting chronic inflammation and inhibiting adipogenesis. These abnormal changes are discussed in the context of possible therapeutic approaches to re-establish normal adipose function and to, thereby, increase insulin sensitivity in type 2 diabetes. Such novel approaches include blockade of ceramide biosynthesis using inhibitors of sphingomyelinase or dihydroceramide desaturase and by antagonism of S1P receptors, such as S1P2

Sphingosine kinases : emerging structure function insights

Sphingosine kinases (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and control fundamental cellular processes, including cell survival, proliferation, differentiation, migration, and immune function. In this review, we highlight recent breakthroughs in the structural and functional characterisation of SK1 and these are contextualised by analysis of crystal structures for closely related prokaryotic lipid kinases. We identify a putative dimerisation interface and propose novel regulatory mechanisms governing structural plasticity induced by phosphorylation and interaction with phospholipids and proteins. Our analysis suggests that the catalytic function and regulation of the enzymes might be dependent on conformational mobility and it provides a roadmap for future interrogation of SK1 function and its role in physiology and disease

Sphingosine 1-phosphate receptors and sphingosine kinase 1 : novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers

There is substantial evidence for a role in cancer of the bioactive lipid sphingosine 1-phosphate (S1P), the enzyme sphingosine kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that sphingosine kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome. These findings suggest that S1P, in addition to being a biomarker of clinical prognosis, might also be a new therapeutic target for intervention in cancer

Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells

Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selective for SK2 whereas the 1-deoxysphinganines 55-21 and 77-7 are selective for SK1. (2S,3R)-1-Deoxysphinganine (55-21) induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitors PF-543 and VPC96091 failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as 55-21 are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders