Bench to Bedside: Signaling

I型神经纤维瘤病（NF 1）影响3500人中的1人，其具有约10%的终生风险 与NF 1相关的恶性肿瘤NF 1的缺失引起多种临床表现，其中一些表现为： 这是毁灭性的。危及生命的表现可能出现在恶性外周血管疾病的进展中 神经肿瘤（MPNSTs）。目前，仅有的治疗方法很少有效。分子上，NF 1导致 Ras癌基因的激活以及在某些情况下cAMP水平的升高。Ras激活导致 刺激介导肿瘤发生的两种信号通路：1类PI 3 K和RAF激酶 信号通路PI 3 K通路的激活导致硬化症复合体的抑制 (TSC)肿瘤抑制因子（TSC 1/2）通过磷酸化TSC 2。反过来，RAF激酶的激活 信号通路诱导两种激酶的顺序刺激，这两种激酶已被证明在24小时内磷酸化/延迟TSC 2。 不同的磷酸化位点，提高了RAF途径也可能介导抑制的可能性。 NF 1中的TSC 1/2。TSC 1/2的抑制增加了Rheb的GTP结合形式，其刺激了细胞的增殖。 哺乳动物雷帕霉素靶蛋白（mTOR），一种大型蛋白激酶。mTOR介导一种蛋白质的磷酸化， 细胞生长中涉及的许多下游底物，如S6激酶1（S6 K1）和起始因子 4 E结合蛋白（4 E-BP 1）。对果蝇和小鼠的研究表明，对TSC 1/2生长的影响 缺陷设置主要通过S6 K1介导。此外，mTOR/S6 K1信号通路也是 受营养物质的调节，我们最近发现，营养途径是通过3类 PI 3 K（hVps 34），其本身由蛋白激酶A（PKA）调节。由于NF 1功能的丧失也会导致 PKA信号的增加，我们的模型是NF 1突变细胞中PKA的激活可能驱动S6 K1的激活 独立于1级PI 3 K或RAF。在这里，我们概述了实验，使我们能够（1） 辨别PI 3 K和RAF通路在NF 1中的作用，（2）PKA活化的重要性， （3）S6 K1在NF 1中介导这些肿瘤反应中的作用。在 长期以来，与辛辛那提神经纤维瘤病研究中心的成员合作，我们建议 开发针对特定细胞蛋白质的靶向治疗，这些蛋白质已知在NF 1病理学中失调。

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.