ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth
ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth
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DOI：
10.1242/jcs.01183
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发表时间：
2004-07-01
影响因子：
4
通讯作者：
Yamamoto, T
中科院分区：
文献类型：
--
作者：
Motegi, A;Fujimoto, J;Yamamoto, T
间变性淋巴瘤激酶（ALK）是一种受体型蛋白酪氨酸激酶，优先在胚胎晚期中枢和周围神经系统的神经元中表达。为了阐明 ALK 在神经元中的作用，我们开发了一种针对 ALK 胞外结构域的激动剂单克隆抗体 (mAb)。在这里，我们证明 mAb16-39 会引发人神经母细胞瘤 (SK-N-SH) 细胞中内源表达的 ALK 的酪氨酸磷酸化。用 mAb16-39 刺激这些细胞可显着诱导胰岛素受体底物 1 (IRS-1)、Shc 和 c-Cbl 的酪氨酸磷酸化，以及它们与 ALK 的相互作用以及 ERK1/2 的激活。此外，我们发现与 mAb16-39 持续孵育可诱导 SK-N-SH 细胞的细胞生长和神经突生长。这些反应可被 MEK 抑制剂 PD98059 完全阻断，但不会被磷脂酰肌醇 3 激酶 (PI 3 激酶) 抑制剂渥曼青霉素阻断，表明丝裂原激活蛋白激酶 (MAP 激酶) 信号级联在 ALK 介导的神经元生长和分化中发挥重要作用。
Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is expressed preferentially in neurons of the central and peripheral nervous systems at late embryonic stages. To elucidate the role of ALK in neurons, we developed an agonist monoclonal antibody (mAb) against the extracellular domain of ALK. Here we show that mAb16-39 elicits tyrosine phosphorylation of endogenously expressed ALK in human neuroblastoma (SK-N-SH) cells. Stimulation of these cells with mAb16-39 markedly induces the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), Shc, and c-Cbl and also their interaction with ALK and activation of ERK1/2. Furthermore, we show that continuous incubation with mAb16-39 induces the cell growth and neurite outgrowth of SK-N-SH cells. These responses are completely blocked by MEK inhibitor PD98059 but not by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, indicating an essential role of the mitogen-activated protein kinase (MAP kinase) signaling cascade in ALK-mediated growth and differentiation of neurons.