In addition, the IPCinduced cardioprotective effect may also result from PKC activation and SPHK activation to enhance intracellular S1P levels in rat heart .
Tissues also generate protective S1P, likely by activation of ceramidase and/or SPHK, during very early phases of ischemia, which may cause transient reduction of ceramide and S1P-induced inhibition of SMase.
Cells were first treated with a selective SphK
inhibitor (iSK, 5 [micro]M), that blocks S1P synthesis, in order to evaluate the contribution of S1P inside-out signalling or with exogenous S1P (exoS1P, 1 [micro]M).
Activation of various plasma membrane receptors, such as the PDGFR [22, 51], the FceRI, and FcyRI  as well as the C5aR , was found to rapidly increase intracellular S1P production through the stimulation of the SphK
. Inhibition of SphK
stimulation strongly reduced or even prevented cellular events such as receptor-stimulated DNA synthesis, [Ca.sup.2+] mobilization, and vesicular trafficking.
The evidence for SphK
inducing production of COX-2 during parturition was uncovered by Serrano-Sanchez et al.
En contraparte, los niveles de S-1-P y la actividad de la enzima esfingosina quinasa, son aumentados, entre otros, por el tratamiento con los factores de crecimiento EGF, PDGF y NGF, cuyo efecto proliferativo es inhibido competitivamente por inhibidores de SphK
, por lo que se ha asociado este esfingolipido a efectos proliferativos (65).
LEC-specific deletion of SphK1 in the SphK2 knockout mouse inhibited lymphatic vessel maturation, indicating that SphKs
and S1P in LECs are required for proper development of lymphatic vessels .
Ceramidases promote carcinogenesis by disturbing the ceramide/S1P ratio, permitting phosphorylation of sphingosine by SPHKs
, and determine the efficacy of cancer therapy.
Sphingosine kinases (SPHK
), including SPHK1 and SPHK2, are a conserved lipid kinase family that catalyzes S1P formation.
FTY720 is now considered as a competitive inhibitor of SphK1 , while some showed that FTY720 could inhibit the activities of both SphK1 and SphK2 and suppress the phosphorylation of sphingosine by SphKs
, resulting in decreased S1P production .
Erythrocytes and platelets are major contributors to blood S1P, as both of these cell types are exposed to circulating sphingosine, contain SphKs
activity, and lack most of the S1P-degrading enzymes [30, 62].
Sphingosine is further converted to S1P by SphKs
. S1P can be converted back to sphingosine by the S1P phosphatase, or it can be irreversibly degraded by S1P lyase to ethanolamine phosphate and hexadecanal (palmitaldehyde).