Figure 4.

SphK1/S1P/S1PR1 feed-forward loop sustain signals promoting colon tumorigenesis.

Notes: SphK1 produces S1P, which is kept in the cell and/or is exported in the extracellular milieu. Extracellular S1P activates S1PR1 which, in turn, activates the JAK2/STAT3 pathway. STAT3 is one of the transcription factors involved in the regulation of IL-6 and S1PR1 expression. Intracellular S1P can activate NFκB, a transcriptional regulator of SphK1. All these pathways are interrelated in an amplification loop, allowing for the sustained activation of STAT3, which is involved in cell transformation and tumor progression. Bent arrows indicate transcriptional regulation.

Abbreviations: SphK, sphingosine kinase; S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor; STAT3, signal transducer and activator of transcription 3; IL, interleukin; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; JAK2, Janus kinase 2; SPNS2, spinster homolog 2; ABC, ATP Binding Cassette; ATP, adenosine triphosphate.