Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
基本信息
- 批准号:10702314
- 负责人:
- 金额:$ 83.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:ActinsAdhesionsAffectApicalAxonBenignBiological ModelsBody RegionsBreastCancer cell lineCell AdhesionCell Cycle ProgressionCell MaturationCell physiologyCell-Cell AdhesionCell-Matrix JunctionCellsCentriolesCiliaColonComplexCongenital AbnormalityCytoplasmic TailDevelopmentDevelopmental ProcessDockingDown SyndromeDsh proteinEmbryoEmbryonic DevelopmentEnzymesEph Family ReceptorsEphrinsEpithelial CellsEventFibroblast Growth FactorFibroblast Growth Factor ReceptorsFrequenciesGTPBP1 geneGleanHumanKnowledgeLaboratoriesLicensingLigandsLinkMale InfertilityMalignant NeoplasmsMalignant neoplasm of gastrointestinal tractMediatingMembraneModificationMorphogenesisMovementNeoplasm MetastasisNeural Crest CellNeuroblastomaPLK1 genePathway interactionsPatientsPatternPhenotypePhosphotransferasesPlayPositioning AttributeProcessProstateProteinsReceptor Protein-Tyrosine KinasesReportingResearchRespiratory DiseaseRetinaRoleScaffolding ProteinSignal PathwaySignal TransductionSignaling MoleculeSpecificityStem Cell DevelopmentSystemTherapeuticTissuesTumor AngiogenesisTumor Cell InvasionTumor Stem CellsTyrosine PhosphorylationVertebratesVisual FieldsWNT Signaling PathwayXenopusXenopus laevisangiogenesisapical membranecell motilityciliopathycilium biogenesisembryonic stem cellepithelial to mesenchymal transitionhindbrainhuman diseasein vivoinsightkinetosomelink proteinlung small cell carcinomamelanomamembermigrationneoplastic celloverexpressionpluripotencyrecruitretinal progenitor cellscaffoldseparaseskeletalstem cell fate specificationstem cellstumortumorigenesis
项目摘要
During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency, epithelial-to- mesenchymal transition, proliferation, migration, and differentiation. Most, if not all, of these events involve modifications of cell-cell and cell-matrix adhesion, and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, are frequently over-expressed in a wide variety of cancers, including breast, small-cell lung and gastrointestinal cancers, melanomas, and neuroblastomas. Using the Xenopus embryonic system, we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion, and that this activity can be modulated by interaction with an activated FGF receptor. The transmembrane ephrinB1 protein is a bi-directional signaling molecule that signals through its cytoplasmic domain to promote cellular movements into the eye field, whereas activation of the fibroblast growth factor receptor (FGFR) represses these movements and retinal fate. In Xenopus embryos, ephrinB plays a role in retinal progenitor cell movement into the eye field through an interaction with the scaffold protein Dishevelled (Dsh). We recently identified Drg1 (Developmentally regulated GTP binding protein 1) as a new but requisite interactor and regulator of Dishevelled (Dvl) for proper ciliogenesis. Dvl is a central scaffold that mediates both canonical and non-canonical Wnt signaling and can decisively orchestrate various developmental and cellular processes. One of these processes is ciliogenesis, and while Dvl is known to be critical for apical docking and planar polarization of basal bodies in ciliated epithelial cells, little mechanistic insight into the players and their roles have been gleaned since this original discovery. We previously reported the identification of Drg1, a little studied GTP-binding protein 1, that interacts with Dvl and localizes it to the basal body region and we provided critical in vivo evidence that a Drg1/Dvl interaction plays a critical role in ciliogenesis. We now show that Ccdc108, a protein linked to male infertility, has an evolutionarily conserved requirement in motile multiciliation. Using Xenopus laevis embryos, Ccdc108 is shown to be required for the migration and docking of basal bodies to the apical membrane in epidermal multiciliated cells (MCCs). We demonstrate that Ccdc108 interacts with the IFTB complex, and governs the centriolar recruitment of IFT while IFT licenses the targeting of Ccdc108 to the cilium. Moreover, Ccdc108 is required for the centriolar recruitment of Drg1 and activated RhoA, factors that help establish the apical actin network in MCCs. Finally, we show that CEP97, which is known as a negative regulator of primary cilia formation, interacts with dual specificity tyrosine phosphorylation regulated kinase 1A (Dyrk1a) to modulate multiciliogenesis. We show that Dyrk1a phosphorylates CEP97, which in turn promotes the recruitment of Polo-like kinase 1 (Plk1), which is a critical regulator of MCC maturation that functions to enhance centriole disengagement in cooperation with the enzyme Separase.Thus, our study reveals that Dyrk1a and CEP97 coordinate with Plk1 to promote Separase function to properly form multicilia in vertebrate MCCs. Our findings on the collaborative role of CEP97 and Dyrk1a in multiciliation may add to our existing knowledge regarding patients with trisomy 21 and therapeutic approaches for the respiratory diseases in patients with ciliopathy and Down syndrome.
在正常发育过程中,许多组织的祖细胞都经历了多能性、上皮细胞向间质细胞转变、增殖、迁移和分化的进行性限制。大多数,如果不是全部,这些事件涉及细胞-细胞和细胞-基质粘附的修饰,这些粘附系统的异常修饰通常与肿瘤的形成有关。Eph家族的受体酪氨酸激酶及其配体ephrin在多种癌症中经常过度表达,包括乳腺癌、小细胞肺癌和胃肠道癌、黑色素瘤和神经母细胞瘤。利用非洲爪蟾胚胎系统,我们已经证明了由ephrinB细胞内结构域介导的信号传导影响细胞间的粘附,并且这种活性可以通过与激活的FGF受体相互作用来调节。跨膜ephrinB1蛋白是一种双向信号分子,通过其细胞质域发出信号,促进细胞运动进入视野,而成纤维细胞生长因子受体(FGFR)的激活抑制这些运动和视网膜命运。在非洲爪蟾胚胎中,ephrinB通过与支架蛋白disheveled (Dsh)的相互作用,在视网膜祖细胞进入视野的过程中发挥作用。我们最近发现Drg1(发育调节GTP结合蛋白1)是一种新的但必需的相互作用因子和disheveled (Dvl)的调节剂,用于正常的纤毛发生。Dvl是一个中心支架,介导规范和非规范Wnt信号,并能决定性地协调各种发育和细胞过程。其中一个过程是纤毛发生,虽然已知Dvl对纤毛上皮细胞的根尖对接和基底的平面极化至关重要,但自这一最初发现以来,对参与者及其作用的机制了解很少。我们之前报道了一种很少被研究的gtp结合蛋白1 Drg1的鉴定,它与Dvl相互作用并将其定位于基底体区域,我们提供了重要的体内证据,证明Drg1/Dvl相互作用在纤毛发生中起着关键作用。我们现在表明,Ccdc108,一种与男性不育相关的蛋白质,在运动多染色体中具有进化保守的要求。利用非洲爪蟾胚胎,Ccdc108被证明是表皮多纤毛虫细胞(epidermal multiciliated cells, mcs)基体迁移和对接到顶膜所必需的。我们证明Ccdc108与IFTB复合物相互作用,并控制IFT的向心招募,而IFT允许Ccdc108靶向纤毛。此外,Ccdc108对于Drg1和活化RhoA的中心粒募集是必需的,这些因子有助于在mcc中建立顶端肌动蛋白网络。最后,我们发现CEP97作为初级纤毛形成的负调节因子,与双特异性酪氨酸磷酸化调节激酶1A (Dyrk1a)相互作用,调节多纤毛形成。我们发现Dyrk1a磷酸化CEP97,进而促进polo样激酶1 (Plk1)的募集,Plk1是MCC成熟的关键调节因子,与酶分离酶合作,增强中心粒脱离。因此,我们的研究揭示了Dyrk1a和CEP97与Plk1协同促进脊椎动物mcc中分离酶功能正确形成多毛。我们关于CEP97和Dyrk1a在多体化中的协同作用的发现可能会增加我们对21三体患者的现有知识以及纤毛病和唐氏综合征患者呼吸系统疾病的治疗方法。
项目成果
期刊论文数量(0)
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Ira Daar其他文献
Ira Daar的其他文献
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{{ truncateString('Ira Daar', 18)}}的其他基金
Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
- 批准号:
8763043 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
- 批准号:
10262044 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Signaling Mechanisms of EphrinB1 in Cell Adhesion, Migration and Invasion
EphrinB1 在细胞粘附、迁移和侵袭中的信号机制
- 批准号:
8552901 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
- 批准号:
9556237 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Signaling Mechanisms of EphrinB1 in Cell Adhesion, Migration and Invasion
EphrinB1 在细胞粘附、迁移和侵袭中的信号机制
- 批准号:
9343751 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Signaling Mechanisms of EphrinB1 in Cell Adhesion, Migration and Invasion
EphrinB1 在细胞粘附、迁移和侵袭中的信号机制
- 批准号:
8349247 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
- 批准号:
7965177 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Signaling Mechanisms of EphrinB1 in Cell Adhesion, Migration and Invasion
EphrinB1 在细胞粘附、迁移和侵袭中的信号机制
- 批准号:
9153726 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Signaling Mechanisms of EphrinB1 in Cell Adhesion, Migration and Invasion
EphrinB1 在细胞粘附、迁移和侵袭中的信号机制
- 批准号:
8763283 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways
EphrinB 与替代信号通路之间的串扰机制
- 批准号:
8937682 - 财政年份:
- 资助金额:
$ 83.28万 - 项目类别:
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