Abstract
Insulin-like growth factor I (IGF-I) has been previously shown to promote survival of oligodendrocyte progenitors; however, the underlying mechanisms are not fully understood. Our aim was to investigate the involvement of phosphatidylinositol 3-kinase (PI3K), MEK1, and Src family tyrosine kinases in IGF-I-mediated oligodendrocyte progenitor survival. In agreement with previous studies, IGF-I promoted cell survival. We show that IGF-I prevented apoptosis induced by growth factor deprivation in a PI3K-dependent and MEK/ERK-independent manner. In addition, IGF-I activated Akt while inhibiting caspase-3 activation, and these effects were reversed by the PI3K inhibitors LY 294002 and wortmannin, but not by the MEK1 inhibitor PD 98059. Interestingly, PP2, a specific Src-like kinase inhibitor, blocked the tyrosine phosphorylation of Src, Fyn, and Lyn and IGF-I-stimulated Akt activation, yet had no significant effects on caspase-3 activation or progenitor survival. To further determine whether Akt is required for IGF-I-mediated survival, oligodendrocyte progenitors were transduced with defective Akt mutants or treated with an Akt inhibitor. Although the Akt mutants and inhibitor decreased Akt activity and reduced basal cell survival, IGF-I could partially rescue oligodendrocyte progenitors by decreasing caspase-3 activation. These results suggest that 1) PI3K is essential for IGF-I-promoted cell survival, 2) downstream activation of Akt-dependent and -independent pathways is involved, and 3) Src-like tyrosine kinases participate in IGF-I-induced Akt activation. Therefore, an unidentified effector(s) of PI3K appears to be involved in conferring complete IGF-I-mediated protection of oligodendrocyte progenitors.
Highlights
Previous work has shown that insulin-like growth factor I (IGF-I)1 is important for the survival of oligodendrocyte pro
The Akt mutants and inhibitor decreased Akt activity and reduced basal cell survival, IGF-I could partially rescue oligodendrocyte progenitors by decreasing caspase-3 activation. These results suggest that 1) phosphatidylinositol 3-kinase (PI3K) is essential for IGF-Ipromoted cell survival, 2) downstream activation of Aktdependent and -independent pathways is involved, and 3) Src-like tyrosine kinases participate in IGF-I-induced Akt activation
In cells grown in DMEM alone, the viability was only 54% of that of the cells grown in serum-free medium (SFM), whereas 100 ng/ml IGF-I increased MTT values to the same levels as those found in SFM (Table I)
Summary
Previous work has shown that insulin-like growth factor I (IGF-I) is important for the survival of oligodendrocyte pro-. One of the crucial downstream targets of PI3K is the serine/ threonine kinase Akt, which is recruited to the membrane by direct binding of its pleckstrin homology domain to the PI3Kproduced phosphatidylinositol 3,4,5-trisphosphate Upstream kinases such as 3-phosphoinositide-dependent kinase (PDK)-1 and PDK2 activate Akt by phosphorylation of Thr308 [21] in its activation loop and Ser473 in the C-terminal regulatory domain [22], respectively. RSK phosphorylates and activates the cAMP response element-binding protein, a transcription factor that mediates cell survival [27,28,29] Both the MEK/ERK and PI3K pathways are required in IGF-I-mediated monocytederived dendritic cell survival [30], and other studies [63,64,65, 67] have elucidated even more complex mechanisms in different cell types. An unidentified effector of PI3K, in addition to Akt, appears to be required to confer full protection of oligodendrocyte progenitors by IGF-I
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