Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways
Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways
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DOI：
10.1038/sj.onc.1210923
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发表时间：
2008-04-24
期刊：
影响因子：
8
通讯作者：
Fernandez-Valle, C.
中科院分区：
文献类型：
--
作者：
Thaxton, C.;Lopera, J.;Fernandez-Valle, C.
神经系统的突变。2型纤维瘤病（NF 2）基因引起神经系统中的神经鞘瘤和其它肿瘤的形成。NF 2蛋白，Schwannomin/Merlin，是一种由丝氨酸518（S518）磷酸化调节的细胞因子相关肿瘤抑制因子。非磷酸化的Schwannomin部分通过抑制Rac和p21激活的激酶（Pak）来限制细胞增殖。在负反馈回路中，Pak磷酸化Schwannomin，使其抑制Pak的能力失活。关于促进Pak活性和Schwannomin磷酸化的受体机制知之甚少。在这里，我们证明在原代雪旺细胞（SC），雪旺蛋白是快速磷酸化的S518由Pak层粘连蛋白-1结合b1整合素，并通过蛋白激酶A神经调节蛋白-1b（NRG 1b）结合ErbB 2/ErbB 3受体。这些受体与磷酸化的Schwannomin、P-Pak、Cdc 42和桩蛋白一起富集在SC过程的远端，并且可以使用b1整联蛋白抗体作为复合物分离。层粘连蛋白-1和NRG 1 β的双重刺激不会协同增加Schwannomin磷酸化，因为ErbB 2激酶部分拮抗Pak的整合素依赖性激活。这些结果确定了两个平行的，但相互作用的途径，抑制肿瘤抑制活性的施万诺明，使亚融合的SC增殖。此外，他们确定ErbB 2，ErbB 3和β 1整合素作为NF 2的潜在治疗靶点。
Mutations in the neuro. bromatosis type 2 (NF2) gene cause formation of schwannomas and other tumors in the nervous system. The NF2 protein, Schwannomin/Merlin, is a cytoskeleton-associated tumor suppressor regulated by phosphorylation at serine 518 (S518). Unphosphorylated Schwannomin restricts cell proliferation in part by inhibiting Rac- and p21-activated kinase (Pak). In a negative-feedback loop, Pak phosphorylates Schwannomin inactivating its ability to inhibit Pak. Little is known about receptor mechanisms that promote Pak activity and Schwannomin phosphorylation. Here we demonstrate in primary Schwann cells (SCs) that Schwannomin is rapidly phosphorylated on S518 by Pak following laminin-1 binding to b1 integrin, and by protein kinase A following neuregulin-1b (NRG1b) binding to ErbB2/ErbB3 receptors. These receptors, together with phosphorylated Schwannomin, P-Pak, Cdc42 and paxillin are enriched at the distal tips of SC processes, and can be isolated as a complex using b1 integrin antibody. Dual stimulation with laminin-1 and NRG1 beta does not synergistically increase Schwannomin phosphorylation because ErbB2 kinase partially antagonizes integrin-dependent activation of Pak. These results identify two parallel, but interactive pathways that inactivate the tumor suppressor activity of Schwannomin to allow proliferation of subconfluent SCs. Moreover, they identify ErbB2, ErbB3 and beta 1 integrins as potential therapeutic targets for NF2.