Bench to Bedside: Signaling

神经纤维瘤病I型(NF1)影响每3500人中的1人，他们有大约10%的终生风险 患上与NF1相关的恶性肿瘤。NF1的缺失会引发各种临床表现，其中一些 这是毁灭性的。恶性周围性病变可出现危及生命的表现 神经肿瘤(MPNST)。目前，唯一有效的治疗方法很少。在分子上，NF1导致 RAS癌基因的激活，在某些情况下，cAMP水平上升。RAS激活会导致 激活两条介导肿瘤发生的信号通路：1类PI3K和RAF激酶 信号通路。PI3K通路激活导致结节性硬化症复合体的抑制 (TSC)肿瘤抑制因子(TSC1/2)通过TSC2的磷酸化。反过来，RAF激酶的激活 途径诱导顺序刺激两个已被证明是磷酸化/晚期TSC2的激酶 不同的磷酸化位点，增加了RAF途径也可能介导抑制 NF1中的TSC1/2。抑制TSC1/2会增加Rheb的GTP结合型，从而刺激 哺乳动物雷帕霉素的靶点(MTOR)，一种大的蛋白激酶。MTOR介导一种蛋白的磷酸化 与细胞生长有关的下游底物的数量，如S6激酶1(S6K1)和启动因子 4E结合蛋白(4E-BP1)。对果蝇和小鼠的研究认为，TSC1/2对生长的影响 缺失的环境在很大程度上是通过S6K1介导的。此外，mTOR/S6K1信号通路也是 受营养物质调节，我们最近发现，营养途径是通过3类物质控制的 PI3K(HVps34)，其本身受蛋白激酶A(PKA)的调节。AS丧失NF1功能也会导致 在PKA信号转导中，我们的模型是NF1突变细胞中PKA的激活可能驱动S6K1的激活 独立于1级PI3K或英国皇家空军。这里我们概述了一些实验，这些实验将使我们能够(1) 认识PI3K和RAF通路在NF1中的作用，(2)PKA激活的重要性， (3)S6K1在NF1中介导这些肿瘤反应的作用。在 长期而言，与辛辛那提神经纤维瘤病研究中心的成员合作，我们建议 开发针对NF1病理中已知的放松调控的特定细胞蛋白的靶向治疗。

Neurofibromatosis type I (NF1) affects 1 out of 3500 individuals, who have an approximate 10% lifetime risk of developing a NF1 related malignancy. Loss of NF1 provokes a variety of clinical manifestations, some of which are devastating. Life threatening manifestations can arise from the progression to malignant peripheral nerve tumors (MPNSTs). Currently the only treatments are only rarely effective. Molecularly, NF1 results in the activation of the Ras oncogene and in some cases a rise in cAMP levels. Ras activation results in the stimulation of two signaling pathways which mediate oncogenesis: the class 1 PI3K and RAF kinase signaling pathways. Activation of the PI3K pathway leads to the inhibition of the Tuberous Sclerosis Complex (TSC) tumor suppressor (TSC1/2) through phosphorylation of TSC2. In turn, activation of the RAF kinase pathway induces the sequential stimulation of two kinases that have been shown to phosphor/late TSC2 at distinct phosphorylation sites, raising the possibility that the RAF pathway may also mediate inhibition of TSC1/2 in NF1. Inhibition of TSC1/2 increases the GTP-bound form of Rheb, which stimulates the mammalian Target Of Rapamycin (mTOR), a large protein kinase. mTOR mediates the phosphorylation of a number of downstream substrates implicated in cell growth, such as S6 kinase 1 (S6K1) and initiation factor 4E binding protein (4E-BP1). Studies in Drosophila and mice argue that the effects on growth in a TSC1/2 deficient setting are largely mediated through S6K1. Moreover the mTOR/S6K1 signaling pathway is also regulated by nutrients, and we have recently found that the nutrient pathway is controlled through class 3 PI3K (hVps34), which itself is regulated by protein kinase A (PKA). As loss of NF1 function also leads to a rise in PKA signaling, our model is that activation of PKA in NF1 mutant cells may drive S6K1 activation independent of the class 1 PI3K or RAF. Here we have outlined experiments which will allow us to (1) discern the contribution of the PI3K and RAF pathways in NF1, (2) the importance of PKA activation, mediated by hVps34, in NF1, and (3) the role of S6K1 in mediating these neoplastic response in NF1. In the long term, working with the members of the Cincinnati Center for Neurofibromatosis Research, we propose to develop targeted therapies against specific cellular proteins known to be deregulated in NF1 pathologies.