Integrin splicing and cancer stem cell fate

整合素剪接和癌症干细胞命运

• 批准号: 9055381
• 负责人: Arthur M Mercurio
• 金额: $ 38.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-28 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055381
• 关键词: Address; Alternative Splicing; Antigen-Antibody Complex; BMI1 gene; Binding; Biology; Breast Carcinoma; Breast Epithelial Cells; Cell Adhesion; Cell membrane; Cells; Complex; Cytoplasmic Tail; Data; Deposition; Development; Event; Feedback; Gap Junctions; Gene Targeting; Genetic Transcription; Growth; Integrin alpha6; Integrin alpha6beta1; Integrins; Laminin; Lead; Ligands; Malignant Epithelial Cell; Mediating; Messenger RNA; Nuclear; Pathway interactions; Phosphorylation; Phosphotransferases; Property; RNA Splicing; Repression; Resistance development; Role; Serine; Signal Repression; Signal Transduction; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Transducers; Tumor Suppressor Proteins; Variant; Vascular Endothelial Growth Factors; Work; adhesion receptor; base; cancer initiation; cancer stem cell; effective therapy; feeding; innovation; kinase inhibitor; malignant breast neoplasm; novel; prevent; public health relevance; stem cell fate; targeted treatment; tumor

 DESCRIPTION (provided by applicant): This proposal will examine the novel hypothesis the genesis and function of breast cancer stem cells (CSCs) are governed by a feed forward loop that sustains activation of the Hippo transducer TAZ. The nexus of this loop is a splice variant of the α6β1 integrin, α6Bβ1. Two variants of the α6 subunit exist (α6A and α6B) that differ onl in their cytoplasmic domains. Alternative splicing of a common mRNA generates these variants. α6Aβ1 integrin signaling prevents TAZ activation. The first aim will pursue the mechanism involved based on the findings that α6Aβ1 interacts with the polarity/tumor suppressor protein Scribble and that Scribble associates with TAZ and prevents its nuclear localization. Thus, the first aim will test the hypothesis that the α6Aβ1 integrin interacts with Scribble on the surfaceof mammary epithelial cells and contributes to its anchoring on the plasma membrane, an interaction mediated by the PDZ-binding domain present in the α6A cytoplasmic domain. It is postulated that the α6A integrin/Scribble complex sequesters TAZ preventing its nuclear localization and activation. The second aim will assess the hypothesis that one mechanism by which TAZ promotes the genesis of CSCs is to repress the mRNA splicing factor ESRP1 resulting in the genesis of α6Bβ1 and loss of α6Aβ1, and the formation of a LM511 matrix. Moreover, it is postulated that TAZ regulates VEGF transcription and induces VEGF signaling, and that VEGF signaling enables the BMI1-mediated repression of ESRP1. TAZ also promotes the formation of a LM511 matrix that functions as the ligand for α6Bβ1. Consequently, a feed forward loop is established involving TAZ and LM511/α6Bβ1 signaling that sustains CSCs. The third specific aim will determine how α6Aβ1 and α6Bβ1 signaling differ in their ability to actiate TAZ focusing on the role of Jun-terminal kinase (JNK). The specific hypothesis to be addressed is that α6Aβ1 signaling promotes JNK activation and JNK-mediated phosphorylation of TAZ on a novel serine (S90), which contributes to TAZ inactivation. LM511/α6Bβ1 signaling, in contrast, prevents JNK activation and JNK-mediated TAZ phosphorylation enabling TAZ activation. This hypothesis infers that JNK inhibition has a causal role in TAZ activation and the acquisition of stem cell properties, which will be evaluated. This proposal is rich in innovation and significance and the results to be obtained will have a major impact on our understanding of the biology of breast CSCs and reveal new mechanisms for therapeutic intervention.

 描述（由应用提供）：该提案将检查新的假设乳腺癌干细胞（CSC）的起源和功能受饲料前回路的控制，该馈电环持续激活了河马传感器TAZ。该循环的下一个是剪接变体 α6β1整合素α6Bβ1。存在α6亚基的两个变体（α6a和α6b）在其细胞质结构域中有所不同。公共mRNA的替代剪接会产生这些变体。 α6Aβ1整合素信号传导可防止TAZ激活。第一个目的将基于α6Aβ1与极性/肿瘤抑制蛋白涂鸦相互作用的发现涉及的机制，并与TAZ相关并防止其核定位。这是第一个目的将检验以下假设：α6Aβ1整合素与乳液上皮细胞表面上的涂鸦相互作用，并有助于其锚定在质膜上，质膜是由存在于α6a细胞质质域中的PDZ结合结构域介导的相互作用。据推测，α6a整合素/涂鸦复合物隔离TAZ阻止其核定位和激活。第二个目的将评估以下假设：TAZ促进CSC的发生的一种机制是反映mRNA剪接因子ESRP1导致α6Bβ1的发生和α6Aβ1的丧失以及LM511矩阵的形成。此外，据张贴TAZ调节VEGF转录并诱导VEGF信号传导，而VEGF信号传导使BMI1介导的ESRP1表示。 TAZ还促进了作为α6Bβ1配体的LM511基质的形成。因此，建立了涉及维持CSC的TAZ和LM511/α6Bβ1信号的馈电回路。第三个特定目标将决定α6Aβ1和α6Bβ1信号传导在其作用于taz的能力上的不同，重点是Jun末端激酶（JNK）的作用。要解决的具体假设是，α6Aβ1信号传导促进了TAZ在新型丝氨酸（S90）上促进JNK激活和JNK介导的磷酸化，这有助于TAZ灭活。相反，LM511/α6Bβ1信号传导可防止JNK激活，JNK介导的TAZ磷酸化可实现TAZ激活。该假设侵入JNK抑制在TAZ激活和干细胞特性的获取中具有因果作用，这将进行评估。该提议丰富了创新和意义 并且要获得的结果将对我们对乳房CSC的生物学的理解产生重大影响，并揭示新的治疗干预机制。