Figure 2.

Functional roles of SphKs and S1P in cells. Upon ERK1/2 mediated phosphorylation/activation in the presence of various agonist (such as TNFα, cytokines and diverse growth factors), SphK1 is translocated to plasma membrane from cytoplasm and interact with calcium-myristoyl switch protein 1 (C1B1). This facilitates the phosphorylation of sphingosine to generate S1P, which can either be secreted out or interacts with intracellular targets (such as TRAF2) to elicit its functions. Once secreted out of the cell, S1P binds to the S1P receptor (S1PR) embedded in the plasma membrane and activates various downstream signaling pathways that control cell survival, proliferation, and migration. In the nucleus, SphK2 catalyzes the phosphorylation of sphingosine to generate S1P that inhibits the activity of histone deacetylases (HDAC1/2) and regulates gene expression. S1P also binds to human telomerase reverse transcriptase (hTERT) at the nuclear periphery in human and mouse fibroblasts that inhibits its interaction with makorin ring finger protein 1 (MKRN1) and promotes telomerase stability. S1P is also produced in the mitochondria by the action of SphK2.