Function of NF2/Merlin in regulation of the Hippo/Salvador/Warts growth control pathway

NF2/Merlin 在调节 Hippo/Salvador/Warts 生长控制通路中的功能

• 批准号: 10826475
• 负责人: Richard G Fehon
• 金额: $ 49.27万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10826475
• 关键词: Actomyosin; Apical; Automobile Driving; Binding; Biological; Caenorhabditis elegans; Cancer Biology; Cells; Complex; Cues; Curiosities; Cytoplasmic Protein; Development; Disease; Drosophila genus; Epithelial Cells; Epithelium; Eukaryota; Feedback; Funding; Genes; Genetic; Goals; Growth; Hepatocarcinogenesis; Human; Intercellular Junctions; Ligands; Malignant Neoplasms; Mammals; Mechanics; Medial; Membrane; Modeling; Molecular; Morphogenesis; Mutation; Natural regeneration; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Oncogenic; Organism; Output; Pathway interactions; Patients; Pattern; Phosphotransferases; Process; Proteins; Regulation; Research; Role; Scaffolding Protein; Signal Pathway; Signal Repression; Signal Transduction; Signal Transduction Pathway; Site; System; Techniques; Testing; Tissues; Transcription Coactivator; Tumor Suppression; Tumor Suppressor Proteins; Work; Yeasts; bilateral vestibular Schwannoma; cell cortex; deafness; disease phenotype; experimental study; extracellular; fascinate; human disease; insight; interest; member; meningioma; morphogens; novel; polarized cell; protein activation; recruit; stem cell biology; targeted treatment; therapy development; tool; tumor; ubiquitin-protein ligase

Project Summary/Abstract Neurofibromatosis type 2 (NF2), a human disease characterized by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other tumors, is caused by loss of the tumor suppressor protein Merlin. Studies using the fruit fly Drosophila and subsequently confirmed in mammalian systems indicate that Merlin is an upstream component of the Hippo pathway, a conserved signal transduction pathway that regulates tissue growth. Mutations in Merlin and other Hippo pathway components are believed to cause tumors because they cause activation of an oncogenic protein Yorkie/YAP and increased expression of growth promoting genes. Identifying specific proteins and signal transduction pathways with which Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. We seek to understand how Merlin and the other HSW components are organized into a signaling complex at the cell cortex and how the activity of this complex is controlled. We have shown that Merlin and its binding partner Kibra nucleate formation of a signaling complex at a site separate from intercellular junctions, and thus that these proteins can function in parallel to another upstream regulator, Expanded. We also have shown that as these proteins assemble a signaling complex, they recruit an E3-ligase complex that degrades Kibra and represses signaling in a negative feedback loop. In the next funding period, we propose that Kibra degradation is promoted by mechanical tension and that this is one mechanism by which tension controls tissue growth. We also plan to test a model we propose in which Kibra and Merlin are recruited to the junctional cortex in an inactive state by the apical polarity protein aPKC in opposition to medial actomyosin networks which facilitate medial accumulation and activation of these proteins. To explore these novel hypotheses, we have developed tools and techniques that allow us to examine the localization and dynamics of Hippo pathway proteins expressed at endogenous levels in living tissues. Using with the exquisite genetic tools available in Drosophila, we can now elucidate the role of each pathway component in assembling and activating the Hippo pathway. These experiments are expected to provide insights into NF2, tumor suppression in general, and the role of actomyosin dynamics in regulating signaling processes. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control tissue growth and determine cell fate during development and regeneration.

项目摘要/摘要 神经纤维瘤病2型(NF2)，是一种以双侧前庭形成为特征的人类疾病 神经鞘瘤(导致耳聋)和其他肿瘤，是由肿瘤抑制因子的缺失引起的 蛋白质梅林。利用果蝇进行的研究，随后在哺乳动物系统中得到证实 表明Merlin是河马途径的上游组成部分，是一种保守的信号转导途径 调节组织生长的途径。Merlin和其他河马途径组件的突变是 被认为会导致肿瘤，因为它们会激活致癌蛋白York kie/YAP和 促进生长的基因表达增加。识别特定蛋白质和信号转导 梅林相互作用的途径特别重要，因为这些伙伴可能作为基因 NF2疾病表型的修饰物，并为治疗药物提供潜在的靶点。 我们试图了解Merlin和其他HSW组件是如何组织成一个信令的 以及这个复合体的活动是如何被控制的。我们已经证明了梅林 和它的结合伙伴Kibra在与 细胞间的连接，因此这些蛋白质可以平行于另一个上游发挥作用 调整器，扩展。我们还表明，当这些蛋白质组装一个信号复合体时，它们 招募一种E3-连接酶复合体，它能降解Kibra并在负反馈循环中抑制信号传递。 在下一个资金期，我们建议通过机械张力和 这是张力控制组织生长的一种机制。我们还计划测试一款我们 建议Kibra和Merlin在非活动状态下由顶端被招募到连接皮质 与促进内侧蓄积的内侧肌球蛋白网络相反的极性蛋白aPKC 以及这些蛋白质的激活。为了探索这些新的假设，我们开发了工具和 使我们能够检查河马途径蛋白的定位和动态的技术 在活体组织中以内源性水平表达。与精致的基因工具一起使用 现在，我们可以阐明每个途径组件在组装和激活 河马路线。这些实验有望提供对NF2，肿瘤抑制在 以及肌动球蛋白动力学在调节信号过程中的作用。最后，这些研究 应该有助于研究细胞相互作用控制组织的机制 在发育和再生过程中，细胞生长和决定细胞命运。

项目成果

Microstructural connectivity of the arcuate fasciculus in adolescents with high-functioning autism.

• DOI: 10.1016/j.neuroimage.2010.01.083
• 发表时间: 2010-07-01
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Fletcher, P. Thomas;Whitaker, Ross T.;Tao, Ran;DuBray, Molly B.;Froehlich, Alyson;Ravichandran, Caitlin;Alexander, Andrew L.;Bigler, Erin D.;Lange, Nicholas;Lainhart, Janet E.
• 通讯作者: Lainhart, Janet E.

Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.

• DOI: 10.1016/j.devcel.2017.02.004
• 发表时间: 2017-03-13
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Su T;Ludwig MZ;Xu J;Fehon RG
• 通讯作者: Fehon RG

Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization.

• DOI: 10.1083/jcb.141.7.1589
• 发表时间: 1998-06-29
• 期刊: The Journal of cell biology
• 作者: LaJeunesse DR;McCartney BM;Fehon RG
• 通讯作者: Fehon RG

Associations between IQ, total and regional brain volumes, and demography in a large normative sample of healthy children and adolescents.

• DOI: 10.1080/87565641003696833
• 发表时间: 2010
• 期刊: Developmental neuropsychology
• 影响因子: 1.5
• 作者: Lange N;Froimowitz MP;Bigler ED;Lainhart JE;Brain Development Cooperative Group
• 通讯作者: Brain Development Cooperative Group

Memory functioning in children and adolescents with autism.

• DOI: 10.1037/a0024935
• 发表时间: 2011-11
• 期刊: Neuropsychology
• 影响因子: 2.4
• 作者: Southwick JS;Bigler ED;Froehlich A;DuBray MB;Alexander AL;Lange N;Lainhart JE
• 通讯作者: Lainhart JE