Molecular Function of the Nf2 Tumor Suppressor, Merlin

Nf2 肿瘤抑制因子 Merlin 的分子功能

• 批准号: 8080370
• 负责人: ANDREA I MCCLATCHEY
• 金额: $ 33.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080370
• 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; public health relevance; radixin protein; receptor; receptor internalization; trafficking; tumor

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.

描述（由申请人提供）：当细胞逃避通常限制其增殖的规则时，癌症就会发展。细胞表面上的生长因子受体提供了细胞及其环境之间的关键接口，并且是第一个内在的控制水平。生长因子通常是连续可用的，因此需要对受体本身进行精致的控制，以确保仅在有必要的情况下（例如在发育，伤口愈合或正常组织周转）时才进行细胞分裂。精心编排了受体在质膜上的分布和聚集。反过来，这通过调节的内吞作用来控制其信号输出和表面丰度。膜与潜在的皮质细胞骨架之间的界面在此编舞中起积极而动态的作用。 2型神经纤维瘤病（NF2）肿瘤抑制剂，Merlin和密切相关的ERM蛋白（Ezrin，radixin和Moesin）位于膜 - 胞骨骨骼界面，并有望通过膜受体组织和信号传导。在该提案的最初资助期间，我们发现Merlin协调了在细胞之间建立稳定的粘附连接（AJ），并在接触细胞中抑制了表皮生长因子受体（EGFR）内在化和信号传导，并在接触细胞中特异性地建立了信号传导，这表明细胞如何实现接触依赖性的现象依赖性的分子解释。最近，我们发现，通过控制EGFR的膜分布，Merlin调节EGFR采用的内吞途径，这反过来又决定了EGFR内吞作用是否被细胞接触阻塞，这表明Merlin控制EGFR是两步机制。最后，我们最近的研究表明，梅林还可以通过类似的机制控制ERBB3的膜分布。因此，梅林有望成为ERBB生长因子受体家族的中心调节剂（EGFR/ERBB1，ERBB2，ERBB3和ERBB4），几乎与所有形式的人类癌症有关。在扩展这一成功的调查途径的应用中，我们提出了一种多方面的方法，以扩展我们对Merlin在控制膜受体分布和信号传导中的分子功能的理解。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Merlin如何稳定AJ并阻止细胞上EGFR内吞作用：细胞接触。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。 公共卫生相关性：我们将进行分子，细胞和体内研究，以检查NF2肿瘤抑制器Merlin的分子功能。具体而言，我们将测试Merlin以接触依赖方式控制EGFR的膜分布和信号传导的假设。我们还将确定Merlin是否通过类似的机制控制ERBB家族成员ERBB3。这些研究将促进我们对NF2的分子原因和ERBB受体生物学的理解，而ERBB受体的生物学已广泛涉及人类癌症。