Metabolism of sphingomyelin by the sphingomyelinase, ceramidase (Cer'ase) and the sphingosine kinase (SK) enzymes results in formation of S1P and receptor activation. Autocrine and paracrine modes of receptor activation have been implied but have yet to be rigorously proven. Critical signaling molecules, such as phospholipase C (PLC), ERK, PI3K, and Akt are activated. Active Akt binds to the receptor and phosphorylates the third intracellular loop, which is essential for Rac activation. Representation of Figure 2. from T. Hla, et al. 2001, Science, 294, pg. 1877. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP26 CPTAC Assay Portal] a60 G protein mediated signaling pathway PW:0000125 Pathway Ontology sphingosine 1-phosphate signaling pathway PW:0000960 Pathway Ontology 11729304 PubMed Lysophospholipids--receptor revelations. Science 2001 Hla T Lee MJ Ancellin N Paik JH Kluk MJ signaling pathway PW:0000003 Pathway Ontology