Sphingosine Kinase 2 Triggers Cell Death

Science's STKE  14 Oct 2003:
Vol. 2003, Issue 204, pp. tw407-TW407
DOI: 10.1126/stke.2003.204.tw407

Liu et al. report that sphingosine kinase 2 (SphK2), despite its sequence similarity to SphK1, promotes apoptosis instead of promoting proliferation as SphK1 does. NIH 3T3 fibroblasts transfected with either SphK1 or SphK2 showed increased sphingosine 1-phosphate (S1P) production, although cells transfected with SphK1 produced higher levels than cells expressing SphK2. Cells expressing SphK2 exhibited increased basal apoptosis and enhanced apoptosis in response to various cellular stresses compared with control cells. Because both SphK1 and SphK2 stimulated S1P production, the increased cell death observed in the SphK2-expressing cells does not appear to involve this enzymatic activity of SphK2. In the pheochromocytoma cell line PC12, SphK1 expression decreased nerve growth factor withdrawal-stimulated apoptosis; whereas expression of SphK2 had the opposite effect of increasing cell death. Furthermore, SphK2 expression increased cell death even in the presence of nuclear growth factor. SphK2 expression stimulated cytochrome c release from the mitochondria and caspase activation. SphK2 expression in mouse embryo fibroblasts deficient in the S1P receptors S1P2 and S1P3, and in which S1P1 signaling was blocked by pertussis toxin, also promoted apoptosis, which further indicated that S1P is not mediating cell death by SphK2. Instead, SphK2 has a BH3 domain like that found in the proapoptotic proteins of the BH3-only family. Consistent with SphK2 acting as a BH3 only proapoptotic protein, SphK2 coimmunoprecipitated with the antiapoptotic protein Bcl-XL, and a fragment of SphK2 containing only the BH3 domain and not the catalytic domain was able to stimulate apoptosis of PC12 and NIH 3T3 cells.

H. Liu, R. E. Toman, S. K. Goparaju, M. Maceyka, V. E. Nava, H. Sankala, S. G. Payne, M. Bektas, I. Ishii, J. Chun, S. Milstein, S. Spiegel, Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J. Biol. Chem. 278, 40330-40336 (2003). [Abstract] [Full Text]