Figure 4. Inside out signaling by S1P.

Binding of growth factors (e.g. EGF) to their tyrosine kinase receptors activates ERK1, which then phosphorylates cytosolic SphK1 leading to its translocation to the plasma membrane where its substrate sphingosine resides. In some cells, SphK2 is at the plasma membrane and can also be activated by ERK1 phosphorylation. Once produced, S1P can be exported out of cells by ABC transporters to activate cell surface S1P receptors in an autocrine or paracrine manner, known as “inside out signaling by S1P”. This leads to activation of mutiple signals downstream of G proteins important for tumorigenesis, including growth, survival, motility, invasion and regulation of gene expression. In many types of cancer cells, SphK2 is predominantly in the nucleus where it produces S1P that inhibits class I HDACs.