Molecular Function of the Nf2 Tumor Suppressor, Merlin

Nf2 肿瘤抑制因子 Merlin 的分子功能

基本信息

批准号：
8676446
负责人：
ANDREA I MCCLATCHEY
金额：
$ 32.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676446
关键词：
Actins Adherens Junction Biology Cell division Cell membrane Cell surface Cells Clathrin Complex Cultured Cells Cytoskeleton Development ERM protein Endocytosis Ensure Environment Epidermal Growth Factor Receptor ErbB4 gene Exhibits Family Family member Funding Goals Growth Factor Growth Factor Receptors Half-Life Heterodimerization Human In Vitro Investigation Ligands Malignant Neoplasms Mediating Membrane Mitogens Modeling Molecular Neuregulins Neurofibromatosis 2 Neurofibromin 2 Normal tissue morphology Output Pathway interactions Patients Play Polyubiquitination Publishing Receptor Aggregation Role Schwann Cells Signal Transduction Sterols Surface Testing Tumor Suppressor Genes Tumor Suppressor Proteins Work Wound Healing base ezrin follow-up in vivo moesin novel prevent radixin protein receptor receptor internalization trafficking tumor

项目摘要

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.

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。细胞表面的生长因子受体提供了细胞与其环境之间的关键界面，是第一个内在控制水平。生长因子通常是连续可用的，因此需要对受体本身进行精确控制，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经过精心设计的。反过来，这通过调节内吞作用控制它们的信号输出和表面丰度。膜和底层皮质细胞骨架之间的界面在这种编排中发挥着积极和动态的作用。 2 型神经纤维瘤病 (NF2) 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，并准备好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 通过抑制表皮生长因子受体 (EGFR) 内化和接触细胞中的信号传导来协调细胞之间稳定的粘附连接 (AJ) 的建立，这为细胞如何作用提供了分子解释。实现接触依赖性增殖抑制现象。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 EGFR 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 ErbB3 的膜分布。因此，Merlin 有望成为生长因子受体 ErbB 家族（EGFR/ErbB1、ErbB2、ErbB3 和 ErbB4）的核心调节因子，这些受体与几乎所有形式的人类癌症有关。在这个应用中，为了扩展这一成功的研究途径，我们提出了一种多方面的方法来扩展我们对 Merlin 在控制膜受体分布和信号传导方面的分子功能的理解。具体来说，我们计划描述 Merlin 如何控制 EGFR 膜分布和内吞作用以及 Merlin 如何在细胞与细胞接触时稳定 AJ 并阻止 EGFR 内吞作用的分子基础。我们还计划确定 Merlin 是否通过类似的机制控制 ErbB3 的表面可用性。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface.

Merlin/ERM 蛋白通过组织质膜：细胞骨架界面来调节生长因子诱导的巨胞饮作用和受体再循环。

DOI：
发表时间：
2018
期刊：
影响因子：
10.5
作者：
Chiasson;Morris, Zachary S;Liu, Ching;Bradford, William B;Koorman, Thijs;McClatchey, Andrea I
通讯作者：
McClatchey, Andrea I

Neurofibromatosis.

神经纤维瘤病。

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
McClatchey; Andrea I
通讯作者：
Andrea I

Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2.

2 型神经纤维瘤病患者当前治疗方法和加速临床试验的共识建议。

DOI：
发表时间：
2012-01
期刊：
影响因子：
0
作者：
Blakeley, Jaishri O;Evans, D Gareth;Adler, John;Brackmann, Derald;Chen, Ruihong;Ferner, Rosalie E;Hanemann, C Oliver;Harris, Gordon;Huson, Susan M;Jacob, Abraham;Kalamarides, Michel;Karajannis, Matthias A;Korf, Bruce R;Mautner, Victor
通讯作者：
Mautner, Victor

Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.

Merlin 缺陷预测 FAK 抑制剂敏感性：合成致死关系。

DOI：
发表时间：
2014-05-21
期刊：
影响因子：
17.1
作者：
Shapiro, Irina M;Kolev, Vihren N;Vidal, Christian M;Kadariya, Yuwaraj;Ring, Jennifer E;Wright, Quentin;Weaver, David T;Menges, Craig;Padval, Mahesh;McClatchey, Andrea I;Xu, Qunli;Testa, Joseph R;Pachter, Jonathan A
通讯作者：
Pachter, Jonathan A

Ezrin-mediated apical integrity is required for intestinal homeostasis.

埃兹蛋白介导的顶端完整性是肠道稳态所必需的。