IGF‐I‐induced oligodendrocyte progenitor proliferation requires PI3K/Akt, MEK/ERK, and Src‐like tyrosine kinases

Insulin‐like growth factor‐I (IGF‐I) is required for the growth of oligodendrocytes, although the underlying mechanisms are not fully understood. Our aim was to investigate the role of phosphatidylinositol 3‐kinase (PI3K), mitogen‐activated protein kinase kinase (MEK1), and Src family tyrosine kinases in IGF‐I‐stimulated proliferation of oligodendrocyte progenitors. IGF‐I treatment increased the proliferation of cultured oligodendrocyte progenitors as determined by measuring incorporation of [3H]‐thymidine and bromodeoxy‐uridine (BrdU). IGF‐I stimulated a transient phosphorylation of 3‐phosphoinositide‐dependent kinase‐1 (PDK1) and extracellular signal‐regulated kinases (ERK1/2) (targets of MEK1), as well as a rapid and sustained activation of Akt (a target of PI3K). Furthermore, inhibitors of PI3K (LY294002 and Wortmannin), MEK1 (PD98059 and U0126), and Src family tyrosine kinases (PP2) decreased IGF‐I‐induced proliferation, and blocked ERK1/2 activation. LY294002, Wortmannin and PP2 also blocked Akt activation. To further determine whether Akt is required for IGF‐I stimulated oligodendrocyte progenitor proliferation, cultures were infected with adenovirus vectors expressing dominant‐negative mutants of Akt or treated with pharmacological inhibitors of Akt. All treatments reduced IGF‐I‐induced oligodendrocyte progenitor proliferation. Our data indicate that stimulation of oligodendrocyte progenitor proliferation by IGF‐I requires Src‐like tyrosine kinases as well as the PI3K/Akt and MEK1/ERK signaling pathways.