IGF-I-induced oligodendrocyte progenitor proliferation requires PI3K/Akt, MEK/ERK, and Src-like tyrosine kinases
IGF-I-induced oligodendrocyte progenitor proliferation requires PI3K/Akt, MEK/ERK, and Src-like tyrosine kinases
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DOI：
10.1111/j.1471-4159.2006.04329.x
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Almazan, Guillermina
中科院分区：
文献类型：
--
作者：
Cui, Qiao-Ling;Almazan, Guillermina
胰岛素样生长因子- i （IGF-I）是少突胶质细胞生长所必需的，尽管其潜在机制尚不完全清楚。我们的目的是研究磷脂酰肌醇3-激酶（PI3K）、丝裂原活化蛋白激酶（MEK1）和Src家族酪氨酸激酶在igf - i刺激的少突胶质细胞祖细胞增殖中的作用。通过测量[H-3]-胸苷和溴脱氧尿苷（BrdU）的掺入，IGF-I处理增加了培养的少突胶质细胞祖细胞的增殖。IGF-I刺激了3-磷酸肌醇依赖性激酶1 （PDK1）和细胞外信号调节激酶（ERK1/2） （MEK1的靶标）的短暂磷酸化，以及Akt （PI3K的靶标）的快速和持续激活。此外，PI3K （LY294002和Wortmannin）、MEK1 （PD98059和U0126）和Src家族酪氨酸激酶（PP2）的抑制剂可降低igf -i诱导的增殖，并阻断ERK1/2的激活。LY294002、Wortmannin和PP2也能抑制Akt的激活。为了进一步确定IGF-I刺激的少突胶质细胞祖细胞增殖是否需要Akt，我们用表达Akt的显性阴性突变体的腺病毒载体感染培养物或用Akt的药理抑制剂处理培养物。所有处理均可降低igf -i诱导的少突胶质细胞祖细胞增殖。我们的数据表明，IGF-I刺激少突胶质细胞祖细胞增殖需要src样酪氨酸激酶以及PI3K/Akt和MEK1/ERK信号通路。
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 [H-3]-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.