Figure 4. Receptor-independent intracellular S1P signalling.

Sphingosine kinase 1 (SPHK1)-generated sphingosine-1-phosphate (S1P) binds TNF receptor-associated factor 2 (TRAF2) to induce polyubiquitylation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which then indirectly mediates nuclear factor-κB (NF-κB) activation¹²¹. S1P also directly associates with peroxisome proliferator-activated receptor-γ (PPARγ), which then mediates the recruitment of PPARγ co-activator 1β (PGC1β) to induce PPARγ-dependent gene expression and neo-angiogenesis¹²⁴. Generation of S1P by SPHK2, which is localized in the nuclear membrane¹²⁷, binds to histone deacetylase 1 (HDAC1) and HDAC2 and inhibits their activity at the nuclear membrane to induce epigenetic regulation of expression ofCDKN1A, which encodes p21, and FOS, which encodes proto-oncogene FOS¹²⁵. SPHK2-generated S1P also binds prohibitin 2 (PHB2) on the mitochondrial membrane to induce cytochromec oxidase (complex IV) activity and mitochondrial respiration¹²⁶. Generation of S1P in the nuclear envelope by SPHK2 results in S1P–telomerase reverse transcriptase (TERT) binding at the nuclear membrane, which then protects telomerase from E3 ubiquitin-protein ligase makorin 1 (MKRN1)-dependent ubiquitylation and degradation, therefore stabilizing telomerase and attenuating senescence induction¹²⁷. This process is mediated by mimicking of TERT phosphorylation upon S1P–TERT binding, and SPHK2 knockdown, genetic loss or pharmacological inhibition using ABC294640 results in rapid telomerase degradation, leading to accelerated senescence and tumour suppression¹²⁷. SPH, sphingosine; Ub, ubiquitin.