The molecular regulation of Gli2 in Hedgehog signaling

Gli2 在 Hedgehog 信号传导中的分子调控

• 批准号: 7060079
• 负责人: BAOLIN WANG
• 金额: $ 31.28万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060079
• 关键词: biological signal transduction; chemical stability; laboratory mouse; phosphorylation; point mutation; proteasome; protein degradation; protein sequence; protein structure function; site directed mutagenesis; transcription factor; ubiquitin

DESCRIPTION (provided by applicant): The Hedgehog (Hh) family of secreted signaling proteins plays fundamental roles in the patterning of ventral neuronal cell types of the brain and spinal cord, limb, and many other structures. Loss of or decrease in the Hh signaling pathway activity results in severe developmental birth defects, whereas inappropriate activation of the Hh signaling pathway is also associated with several common types of human cancer including basal cell carcinoma and medulloblastoma. A thorough understanding of this pathway is crucial for prevention or remedy of the abnormalities resulting from defective or unregulated Hh pathway activation. In vertebrates, Hh signal is mediated by three members of the Gli/Ci family of transcription factors: Glil, Gli2, and Gli3. Genetic analysis has underlined the biological roles of each of the three genes. Glil is a Hh target and a strong transcriptional activator but not essential for the Hh signal transduction in the mouse. Gli2, acting positively, is absolutely required for mediating Hh signal. Gli3 mainly plays a negative role in the pathway. Consistent with this, the majority of Gli3 protein is processed in the absence of Hh signal. In contrast to Gli3, little is known about how the activity of Gli2 protein is regulated at the molecular level. The objective of this application is to understand the molecular mechanism by which Gli2 is regulated. Our preliminary studies have provided the evidence that although Gli2 and Gli3 are phosphorylated similarly by PKA, CKI and GSK3, unlike Gli3, Gli2 undergoes degradation instead processing. The degradation of Gli2 is likely mediated by the ubiquitin and proteasome system through B-TrCP. This application focuses on three aims. 1) Elucidate the molecular mechanism of Gli2 degradation; 2) Determine the role of Shh signaling in the regulation of Gli2 stability and the significance of Gli2 phosphorylation and degradation; and 3) Understand the molecular basis of the distinct fate of Gli2 and Gli3 proteins. The completion of the proposed study will significantly advance our understanding of the molecular mechanism of how Gli2 transcription factor is regulated and how it may mediate Shh signal. It may also give us insight into the understanding of molecular mechanism of human birth defects and cancer associated with abnormal Shh signaling. In addition, it may reveal a novel mechanism by which Beta-TrCP regulates Gli2 degradation and possibly Gli3 processing.

描述（由申请人提供）：分泌信号蛋白的刺猬（HH）家族在大脑和脊髓，肢体和许多其他结构的腹侧神经元细胞类型的图案中起着基本作用。 HH信号通路活动的丧失或减少会导致严重的发育出生缺陷，而HH信号通路的不当激活也与几种常见的人类癌症类型的人类癌症相关，包括基底细胞癌和髓母细胞瘤。对该途径的透彻理解对于预防或不受管制的HH途径激活导致的异常情况至关重要。在脊椎动物中，HH信号由转录因子的GLI/CI家族的三个成员介导：GLIL，GLI2和GLI3。遗传分析强调了这三个基因中每个基因的生物学作用。 GLIL是HH靶标和强的转录激活剂，但对于小鼠中HH信号转导并不是必需的。 Gli2, acting positively, is absolutely required for mediating Hh signal. GLI3主要在途径中起负面作用。与此相一致，大多数GLI3蛋白是在没有HH信号的情况下处理的。与GLI3相反，关于Gli2蛋白在分子水平上如何调节Gli2蛋白的活性知之甚少。该应用的目的是了解调节GLI2的分子机制。我们的初步研究提供了一个证据，尽管GLI2和GLI3被PKA，CKI和GSK3类似地磷酸化，但与GLI3不同，GLI2经历降解而不是处理。 GLI2的降解可能是由泛素和蛋白酶体系统通过B-TRCP介导的。该应用程序侧重于三个目标。 1）阐明Gli2降解的分子机制； 2）确定SHH信号在GLI2稳定性调节中的作用以及GLI2磷酸化和降解的重要性； 3）了解Gli2和Gli3蛋白不同命运的分子基础。拟议研究的完成将显着提高我们对GLI2转录因子的分子机制的理解，以及它如何介导SHH信号。它也可能使我们深入了解与异常SHH信号相关的人类先天缺陷和癌症分子机制的理解。此外，它可能揭示了一种新的机制，通过该机制，β-TRCP调节GLI2降解和可能的GLI3处理。