Role of the candidate protein methyltransferase METTL18 in cancer biology

项目摘要 共价翻译后蛋白质修饰有助于细胞生理学的方方面面 是哺乳动物蛋白质功能多样性的主要来源。对生物多样性的异常调节 这些修饰，以及产生它们的酶，是人类的共同特征 疾病，包括癌症。有150多种蛋白质甲基转移酶编码在 人类基因组，以及越来越多的人类蛋白质，包括几个已建立的 在信号和癌症中的作用，已知含有功能性翻译后甲基化 事件。大多数甲基化事件发生在赖氨酸或精氨酸残基上；然而，我们的实验室和 其他人最近发现，组氨酸甲基化发生在200多种人类蛋白质上， 井。尽管如此，人们对分子、信号和生物学后果知之甚少。 与蛋白质组氨酸甲基化有关。这项提案的重点是一种蛋白质组氨酸 甲基转移酶(PHMT)、METTL18及其在癌症中的作用。在前期工作中，我发现 在许多细胞系中，METTL18甲基化位于His245位的核糖体蛋白rpL3 老鼠组织。我也有证据表明，METTL18调节蛋白质合成和肿瘤发生。 在这里，我建议使用多学科的方法，包括生化、蛋白质组学和细胞 生物学策略：(1)研究METTL18催化的分子和生物学功能 (2)研究了METTL18在胃癌中的生理作用。 拟议的项目将在斯坦福的戈扎尼博士的实验室执行。 大学。Gozani博士是一位经验丰富的导师和领导者，在以下领域的交叉领域 蛋白质甲基化与癌症生物学。他和斯坦福大学生物系 非常适合支持我的研究项目和研究生教育。

Project Summary Covalent post-translational protein modifications contribute to all aspects of cell physiology and are a primary source of protein functional diversity in mammals. The aberrant regulation of these modifications, as well as the enzymes that generate them, is a common feature of human disease, including cancer. There are more than 150 protein methyltransferases encoded in the human genome, and a growing number of human proteins, including several with established roles in signaling and cancer, are known to harbor functional post-translational methylation events. Most methylation events occur on either lysine or arginine residues; however, our lab and others have recently discovered that histidine methylation occurs on over 200 human proteins as well. Still, very little is known about the molecular, signaling and biological consequences associated with protein histidine methylation. This proposal focuses on a protein histidine methyltransferase (PHMT), METTL18, and its role in cancer. In preliminary work I found that METTL18 methylates the ribosomal protein rpL3 at position His245 in numerous cell lines and mouse tissue. I also have evidence that METTL18 regulates protein synthesis and oncogenesis. Here I propose to use multi-disciplinary approaches, including biochemical, proteomic and cell biological strategies to (1) investigate the molecular and biological function of METTL18 catalytic activity and (2) characterize the physiologic role of METTL18 in gastric cancer. The proposed project will be executed in the laboratory of Dr. Or Gozani at Stanford University. Dr. Gozani is an experienced mentor and a leader at the intersection of the fields of protein methylation and cancer biology. He and the Stanford University Department of Biology are well-suited to support my research project and graduate education.