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Novel role of sphingosine kinase 1 as a mediator of neurotrophin‐3 action in oligodendrocyte progenitors
Author(s) -
Saini Harsimran S.,
Coelho Rochelle P.,
Goparaju Sravan K.,
Jolly Puneet S.,
Maceyka Michael,
Spiegel Sarah,
SatoBigbee Carmen
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03451.x
Subject(s) - oligodendrocyte , microbiology and biotechnology , biology , sphingosine , sphingosine kinase , creb , forskolin , phosphorylation , sphingosine kinase 1 , sphingosine 1 phosphate , myelin , endocrinology , biochemistry , transcription factor , stimulation , receptor , gene , central nervous system
We had found previously that neurotrophin‐3 (NT‐3) is a potent stimulator of cAMP‐response element binding protein (CREB) phosphorylation in cultured oligodendrocyte progenitors. Here, we show that CREB phosphorylation in these cells is also highly stimulated by sphingosine‐1‐phosphate (S1P), a sphingolipid metabolite that is known to be a potent mediator of numerous biological processes. Moreover, CREB phosphorylation in response to NT‐3 involves sphingosine kinase 1 (SphK1), the enzyme that synthesizes S1P. Immunocytochemistry and confocal microscopy indicated that NT‐3 induces translocation of SphK1 from the cytoplasm to the plasma membrane of oligodendrocytes, a process accompanied by increased SphK1 activity in the membrane fraction where its substrate sphingosine resides. To examine the involvement of SphK1 in NT‐3 function, SphK1 expression was down‐regulated by treatment with SphK1 sequence‐specific small interfering RNA. Remarkably, the capacity of NT‐3 to protect oligodendrocyte progenitors from apoptotic cell death induced by growth factor deprivation was abolished by down‐regulating the expression of SphK1, as assessed by terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) assay. Altogether, these results suggest that SphK1 plays a crucial role in the stimulation of oligodendrocyte progenitor survival by NT‐3, and demonstrate a functional link between NT‐3 and S1P signaling, adding to the complexity of mechanisms that modulate neurotrophin function and oligodendrocyte development.