SPHK2

Case study 1: Francis R LeBlanc, 2020

Sphingolipid metabolism is increasingly recognised as a therapeutic target in cancer due to its regulation of cell proliferation and apoptosis. The sphingolipid rheostat is proposed to control cell fate through maintaining balance between pro-apoptotic and pro-survival sphingolipids. This balance is regulated by metabolising enzymes involved in sphingolipid production. One such enzyme, sphingosine kinase-2 (SPHK2), produces pro-survival sphingosine 1-phosphate (S1P) by phosphorylation of pro-apoptotic sphingosine.

Here, the researchers examined SPHK2 expression in LGL leukaemia and found SPHK2 mRNA and protein upregulation in a majority of LGL leukaemia patient samples. Knockdown of SPHK2 with siRNA in LGL leukaemia cell lines decreased proliferation. Additionally, the use of ABC294640 or K145, both SPHK2-specific inhibitors, decreased viability of LGL leukaemia cell lines. Mechanistically, SPHK2 inhibition downregulated pro-survival myeloid cell leukaemia-1 (Mcl-1) protein through proteasomal degradation. Targeting of SPHK2 therefore provides a novel therapeutic approach for the treatment of LGL leukaemia.

Fig1. Immunoblot analysis of SPHK2 levels in siRNA-transfected NKL.

Fig2. NKL cells were treated with DMSO or 25 μM of ABC294640 for 3 hours and then cycloheximide (50 μg / mL) was added.

Case study 2: Heidi A Neubauer, 2016

While both human sphingosine kinases (SK1 and SK2) catalyze the generation of the pleiotropic signaling lipid sphingosine 1-phosphate, these enzymes appear to be functionally distinct. The roles of SK2, and its contribution to cancer are much less clear. The team's analysis of gene expression data revealed that SK2 is upregulated in many human cancers, but only to a small extent. Based on these findings, the researchers examined the effect of different levels of cellular SK2 and showed that high-level overexpression reduced cell proliferation and survival, and increased cellular ceramide levels. In contrast, however, low-level SK2 overexpression promoted cell survival and proliferation, and induced neoplastic transformation in vivo. These findings coincided with decreased nuclear localization and increased plasma membrane localization of SK2, as well as increases in extracellular S1P formation.

Fig3. Lysates from the NIH3T3 vector or SK2-overexpressing cell lines were subjected to immunoblot analyses and probed with antibodies against phospho-AKT, total AKT, phospho-ERK1/2, total ERK1/2, FLAG, GFP, SK1 and α-tubulin.

Fig4. The subcellular localization of FLAG-tagged SK2 (red) in the NIH3T3 stable 'low' and 'high' SK2-overexpressing cells was examined by immunofluorescence staining, using FLAG antibody.

Fig1. Proposed scheme for the role of SphK2 in exhibiting the dual antiapoptotic and proapoptotic effects in response to cell stresses. (Leili Hasanifard, 2019)

Fig2. Model for antitumor activity of opaganib. (Lynn W Maines, 2023)

SPHK2 involved in several pathways and played different roles in them. We selected most pathways SPHK2 participated on our site, such as Sphingolipid metabolism, Metabolic pathways, Calcium signaling pathway, which may be useful for your reference. Also, other proteins which involved in the same pathway with SPHK2 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

SPHK2 has several biochemical functions, for example, ATP binding, D-erythro-sphingosine kinase activity, Ras GTPase binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SPHK2 itself. We selected most functions SPHK2 had, and list some proteins which have the same functions with SPHK2. You can find most of the proteins on our site.

SPHK2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SPHK2 here. Most of them are supplied by our site. Hope this information will be useful for your research of SPHK2.

FYN; LYN; FHL2; hemL; astD