Molecular Function of the Nf2 Tumor Suppressor, Merlin

描述（由申请人提供）：当细胞逃避通常限制其增殖的规则时，癌症就会发生。细胞表面上的生长因子受体提供细胞与其环境之间的关键界面，并且是第一内在控制水平。生长因子通常是连续可用的，需要对受体本身进行精密控制，以确保细胞分裂仅在必要时进行，例如在发育、伤口愈合或正常组织更新期间。受体在质膜上的分布和聚集是精心设计的;这反过来又通过受调节的内吞作用控制它们的信号输出和表面丰度。细胞膜和底层皮层细胞骨架之间的界面在这种编排中起着积极和动态的作用。神经纤维瘤病2型（NF 2）肿瘤抑制因子Merlin和密切相关的ERM蛋白（Ezrin，Radixin和Moesin）定位于膜-细胞骨架界面，并准备组织膜受体的分布和信号传导。在该提案的初始资助期间，我们发现Merlin协调细胞之间稳定粘附连接（AJs）的建立，并抑制表皮生长因子受体（EGFR）内化和接触细胞中的信号传导，这表明细胞如何实现接触依赖性增殖抑制现象的分子解释。最近我们发现，通过控制EGFR的膜分布，Merlin调节EGFR的内吞途径，这反过来又决定了EGFR的内吞作用是否被细胞接触阻断，这表明Merlin控制EGFR的两步机制。最后，我们最近的研究表明，Merlin也可能通过类似的机制控制ErbB 3的膜分布。因此，Merlin有望成为ErbB家族生长因子受体（EGFR/ErbB 1、ErbB 2、ErbB 3和ErbB 4）的中心调节剂，这些受体几乎参与所有形式的人类癌症。在这个应用程序中，以扩大这一成功的调查途径，我们提出了一个多方面的方法，以扩大我们的理解梅林在控制膜受体分布和信号的分子功能。具体而言，我们计划描绘梅林如何控制EGFR膜分布和内吞作用的分子基础，以及梅林如何在细胞：细胞接触时稳定AJs并阻断EGFR内吞作用。我们还计划确定Merlin是否通过类似的机制控制ErbB 3的表面可用性。 公共卫生相关性：我们将进行分子、细胞和体内研究，以检查Nf 2肿瘤抑制因子Merlin的分子功能。具体而言，我们将检验Merlin以接触依赖性方式控制EGFR的膜分布和来自EGFR的信号传导的假设。我们还将确定Merlin是否通过类似的机制控制ErbB家族成员ErbB 3。这些研究将促进我们对NF 2的分子原因以及与人类癌症广泛相关的ErbB受体生物学的理解。

DESCRIPTION (provided by applicant): Cancer develops when cells evade the rules that normally limit their proliferation. Growth factor receptors on the cell surface provide a critical interface between the cell and its environment and are the first intrinsic level of control. Growth factors are often continuously available, necessitating exquisite control of the receptors themselves to ensure that cell division proceeds only when warranted, for example during development, wound healing or normal tissue turnover. The distribution and aggregation of receptors across the plasma membrane is exquisitely choreographed; this, in turn, controls their signaling output and surface abundance via regulated endocytosis. The interface between the membrane and the underlying cortical cytoskeleton plays an active and dynamic role in this choreography. The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, and closely related ERM proteins (Ezrin, Radixin and Moesin), localize to the membrane-cytoskeleton interface and are poised to organize the distribution of, and signaling by, membrane receptors. During the initial funding of this proposal, we discovered that Merlin coordinates the establishment of stable adherens junctions (AJs) between cells with the inhibition of Epidermal Growth Factor Receptor (EGFR) internalization and signaling specifically in contacting cells, suggesting a molecular explanation for how cells achieve the phenomenon of contact-dependent inhibition of proliferation. More recently we have found that, by controlling the membrane distribution of EGFR, Merlin regulates the endocytic pathway taken by EGFR, which, in turn, dictates whether EGFR endocytosis is blocked by cell contact, suggesting a two-step mechanism whereby Merlin controls EGFR. Finally, our most recent studies suggest that Merlin may also control the membrane distribution of ErbB3 via a similar mechanism. Thus Merlin is poised to be a central regulator of the ErbB family of growth factor receptors (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4) that have been implicated in nearly all forms of human cancer. In this application to extend this successful avenue of investigation we propose a multifaceted approach to extending our understanding of the molecular function of Merlin in controlling membrane receptor distribution and signaling. Specifically we plan to delineate the molecular basis of how Merlin controls EGFR membrane distribution and endocytosis and how Merlin stabilizes AJs and blocks EGFR endocytosis upon cell:cell contact. We also plan to determine whether Merlin controls the surface availability of ErbB3 via a similar mechanism. PUBLIC HEALTH RELEVANCE: We will carry out molecular, cellular and in vivo studies to examine the molecular function of the Nf2 tumor suppressor, Merlin. Specifically, we will test the hypothesis that Merlin controls the membrane distribution of and signaling from EGFR in a contact- dependent manner. We will also determine whether Merlin controls the ErbB family member ErbB3 via a similar mechanism. These studies will advance our understanding of the molecular cause of NF2 and of the biology of ErbB receptors that have been widely implicated in human cancer.