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Sphingosine signaling. (A) During canonical signaling, when TRAF2 binds to the TNF-α receptor, it recruits SPHK1. SPHK1 catalyzes S1P formation. S1P then acts as a cofactor for TRAF2-mediated K63-linked polyubiquitination of RIP1. (B) S1P also activates ERK1/2 and these together further activate SPHK1. ERK1/2 activation leads to activation of IKK and increased TNF-α production, increasing total flow through the canonical pathway. P, phosphate; U, ubiquitin.
