Regulation of the ERK signaling pathway by K63-linked polyubiquitination

K63 连接的多聚泛素化对 ERK 信号通路的调节

基本信息

批准号：
10535249
负责人：
Xiaolu Yang
金额：
$ 40.46万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535249
关键词：
Address Amino Acid Motifs BRAF gene Biochemical Biology Cell Line Cells Deubiquitinating Enzyme Development Drug Targeting Drug resistance Etiology Eukaryota Extracellular Signal Regulated Kinases FDA approved Goals Guanosine Triphosphate Phosphohydrolases Human Hyperactivity Knowledge Light Link MAP Kinase Kinase Kinase MAP3K1 gene MAPK1 gene MAPK3 gene MEKs Malignant Neoplasms Mammalian Cell Melanoma Cell Metastatic Melanoma Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modification Molecular Mutation Normal Cell Oncogenic Pathogenesis Pathologic Processes Pathway interactions Patients Phosphorylation Phosphotransferases Physiological Processes Polyubiquitin Polyubiquitination Post-Translational Protein Processing Prevalence Proteins Receptor Protein-Tyrosine Kinases Regulation Resistance Role Sampling Signal Pathway Signal Transduction Site Specific qualifier value Specificity Stimulus TRIM Motif Testing Tumor Suppressor Proteins Ubiquitination Unresectable Work Xenograft procedure anticancer research base cancer cell cancer therapy cell behavior effective therapy extracellular inhibitor insight melanoma novel overexpression patient derived xenograft model protein function prototype resistance mechanism response therapy resistant tumor tumorigenesis ubiquitin ligase upstream kinase virtual

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this application is to elucidate the mechanism of Lys63 (K63)-linked polyubiquitination of extracellular signal-regulated kinases ERK1 and ERK2, and to determine the contribution of this novel post-translational modification to tumorigenesis. ERK1 and ERK2, which share high structural and functional similarities, are downstream effectors of a mitogen-activated protein kinase (MAPK) cascade that dictates cellular behavior and cell fate decisions in response to a wide range of intracellular signals. The ERK signaling pathway is the primary mitogenic pathway in mammalian cells. It is aberrantly upregulated in a large fraction of human tumors due to prevalence of mutations in the upstream signaling components, and reactivation of ERK is also the most common mechanism for resistance to drugs that target these upstream components. Developing a therapy that is applicable for the wide range of tumors driven by a hyperactive ERK pathway and that can circumvent drug resistance remains a major challenge in cancer research. To contend with this challenge requires a comprehensive understanding of how ERK is specifically and efficiently activated within the MAPK cascade. The current knowledge of ERK activation is largely limited to their phosphorylation by the upstream kinase MEK. In our preliminary studies, we have found that ERK is conjugated to K63-linked polyubiquitin chains, and that this post-translational modification correlates with ERK activation. Furthermore, we have identified the tripartite-motif protein TRIM15 as a ubiquitin ligase, and the tumor suppressor CYLD as a deubiquitinating enzyme (DUB), that may dynamically regulate ERK ubiquitination. Here we will test the central hypothesis that K63 ubiquitination of ERK is critical for the specific and efficient activation of these kinases and that dysregulation of this post-translational modification contributes to the pathogenesis and therapeutic resistance of tumors. We propose three specific aims. First, we will characterize the role of TRIM15 and CYLD in K63 ubiquitination of ERK and define how their interactions with ERK are regulated by mitogenic stimuli. Second, we will elucidate the function and mechanism of K63 ubiquitination in the activation of ERK. Third, we will determine the role of TRIM15 and CYLD in tumorigenesis and therapeutic resistance. Collectively, these aims will address fundamental issues in ERK biology and oncogenic signaling, and will provide valuable information for the development of effective therapies for the plethora of human tumors that are driven by a hyperactive ERK signaling pathway.

项目概要/摘要本申请的总体目标是阐明 Lys63 (K63) 连接的多泛素化机制细胞外信号调节激酶 ERK1 和 ERK2，并确定这种新型翻译后的贡献改变肿瘤发生。 ERK1 和 ERK2 具有高度的结构和功能相似之处是丝裂原激活蛋白激酶（MAPK）级联的下游效应子，决定了细胞行为和细胞命运决定响应广泛的细胞内信号。 ERK信号传导途径是哺乳动物细胞中主要的有丝分裂途径。它在很大一部分中异常上调由于上游信号成分突变和 ERK 重新激活而导致的人类肿瘤也是对针对这些上游成分的药物产生耐药性的最常见机制。发展一种适用于由过度活跃的 ERK 通路驱动的多种肿瘤的疗法，并且可以规避耐药性仍然是癌症研究的主要挑战。为了应对这一挑战需要全面了解 ERK 如何在 MAPK 内特异性且有效地激活级联。目前对 ERK 激活的了解在很大程度上仅限于上游的磷酸化激酶 MEK。在我们的初步研究中，我们发现 ERK 与 K63 连接的多聚泛素链缀合，并且这种翻译后修饰与 ERK 激活相关。此外，我们还确定了三联基序蛋白 TRIM15 作为泛素连接酶，肿瘤抑制因子 CYLD 作为去泛素化酶酶（DUB），可以动态调节 ERK 泛素化。在这里我们将检验中心假设 ERK 的 K63 泛素化对于这些激酶的特异性和有效激活以及失调至关重要这种翻译后修饰有助于肿瘤的发病机制和治疗耐药性。我们提出三个具体目标。首先，我们将描述 TRIM15 和 CYLD 在 K63 泛素化中的作用 ERK 并定义它们与 ERK 的相互作用如何受到有丝分裂刺激的调节。其次，我们要阐明 K63泛素化在ERK激活中的作用和机制。第三，我们将确定角色 TRIM15 和 CYLD 在肿瘤发生和治疗耐药中的作用。总的来说，这些目标将解决 ERK 生物学和致癌信号传导的基本问题，将为开发针对由高活性 ERK 驱动的多种人类肿瘤的有效疗法信号通路。