Elucidation of NF2's tumor supressive function

描述（由申请人提供）：2型神经纤维瘤病（NF2）是一种以第八脑神经雪旺细胞瘤为特征的遗传性疾病。NF2基因编码一种名为merlin的蛋白质，该蛋白质与ERM蛋白（moesin， ezrin和radixin）高度相关。Merlin被Paks磷酸化，Paks与活化的（gtp结合的）Rac/Cdc42结合，并作为它们的直接效应物。最近的数据表明，merlin通过直接与Paks相互作用和抑制Paks负向调节Rac/cdc42信号。该项目旨在确定merlin的pak抑制功能是否也是merlin的肿瘤抑制功能。此外，细胞和动物模型将被用来测试抑制Pak功能是否可以逆转由NF2缺乏引起的转化和癌症表型。最后，将进行实验以确定可能有助于NF2肿瘤抑制功能的其他机制。综上所述，这些研究将有助于更好地了解merlin的肿瘤抑制功能。这些研究证实Paks是抑制的潜在靶点，将直接为治疗2型神经纤维瘤病的治疗方法的发展指明方向。

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene encodes a protein named merlin, which is highly related to the ERM proteins (moesin, ezrin and radixin). Merlin is phosphorylated by Paks, which bind to activated (GTP-bound) Rac/Cdc42 and function as their direct effectors. Recent data implicate that merlin negatively regulates Rac/cdc42 signaling by directly interacting with and inhibiting Paks. The proposed project is geared towards establishing whether the Pak-inhibitory function of merlin is also merlin's tumor suppressive function. Furthermore, cellular and animal models will be employed to test whether inhibiting Pak function can reverse the transformed and cancer phenotypes that arise from NF2 deficiency. Finally, experiments will be carried out to identify additional mechanisms that may contribute to NF2 tumor suppressor function. Taken together, these studies will lead to a better understanding of merlin's tumor suppressive function. The validation of Paks as potential targets for inhibition, stemming from these studies, will point directly at approaches for the development of therapeutics towards the treatment of neurofibromatosis type 2.