Molecular mechanisms of auxin response

生长素反应的分子机制

• 批准号: 10404759
• 负责人: WILLIAM M GRAY
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404759
• 关键词: ATP phosphohydrolase; Address; Affect; Arabidopsis; Auxins; Binding Proteins; Biological Models; Biology; Cardiovascular Diseases; Cell Size; Cell membrane; Cell physiology; Cells; Data Set; Defect; Development; Diabetes Mellitus; Disease; Eukaryota; Exhibits; Fiber; Food; Genes; Genetic; Goals; Growth; Growth and Development function; Health; Hormones; Human; Human Development; Link; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Orthologous Gene; Pharmacologic Substance; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Plant Model; Plant Sources; Plants; Play; Process; Protein Dephosphorylation; Proteins; Proton-Translocating ATPases; RNA; Regulation; Repression; Research; Role; Serine/Threonine Phosphorylation; Signal Transduction; Somatotropin; Stress; Work; enzyme activity; human disease; novel; novel strategies; organ growth; overexpression; phosphoproteomics; plant growth/development; protein phosphatase 2C; relating to nervous system; response; tool

PROJECT SUMMARY Reversible serine/threonine phosphorylation of proteins plays an essential regulatory function in numerous cellular processes. Type 2C protein phosphatases (PP2Cs) comprise a major class of Ser/Thr phosphatases (PPases), and defects in several human PP2Cs have been implicated in cancer, diabetes, cardiovascular disease, neural disorders, and stress signaling. However, major gaps exist in understanding how PP2C enzyme activity is regulated and what specific proteins and processes are under PP2C control. In plants, PP2C.D PPases inhibit organ growth by repressing cell expansion. In part, this is accomplished by dephosphorylation of a key regulatory phosphosite of plasma membrane (PM) H+-ATPases. The growth hormone auxin stimulates cell expansion by inducing expression of Small Auxin Up RNA (SAUR) genes, which encode novel proteins that bind to PP2C.D PPases to inhibit enzymatic activity. The long-term goal of this project is to thoroughly understand the molecular mechanisms underlying auxin-mediated control of plant growth and development. More specifically, the work described in this proposal will identify regulators and downstream effectors of SAUR-PP2C.D signaling hubs involved in auxin-mediated cell expansion and the integration of volumetric changes with diverse cellular processes to yield a coordinated growth response. Phosphoproteomic studies have identified >140 proteins exhibiting altered phosphorylation in response to auxin. This dataset overlaps substantially with phosphoproteins affected by SAUR overexpression, implicating SAUR-PP2C.D modules as major regulators of the auxin phosphorylome during cell expansion. Using the powerful genetic system of the model plant Arabidopsis, the proposed studies will investigate the functional roles of select phosphoprotein candidates in auxin-induced growth and their regulatory interactions with SAUR- PP2C.D modules. Detailed analysis of auxin’s regulation of PM H+-ATPase activity will also be conducted. Auxin both inhibits H+-ATPase dephosphorylation via SAUR repression of PP2C.D activity and stimulates activation by promoting ATPase phosphorylation by TMK1 and additional kinases, including orthologs of WNK and SPAK/OSR kinases implicated in mammalian cell size control. All of these kinases interact with one another and PP2C.D PPases, and research will address how kinase and phosphatase activities are coordinated and mutually regulated. This work will elucidate PP2C functions and regulatory mechanisms, identify PP2C.D effectors that modulate cell expansion, and illuminate how auxin coordinates diverse cellular processes to control cell size. Given the conservation of PP2C function across kingdoms and the universal process of cell size control, project findings will have broad impact, including implications into human development and disease. Further, as humans depend on plants for sources of food, fiber, and pharmaceuticals, the proposed studies will elucidate plant growth control by SAUR-PP2C.D regulatory modules and facilitate novel strategies for manipulating plant growth to benefit human health.

项目概要 蛋白质的可逆丝氨酸/苏氨酸磷酸化在许多细胞中发挥着重要的调节功能。 细胞过程。 2C 型蛋白磷酸酶 (PP2C) 包含一类主要的 Ser/Thr 磷酸酶 （PPase），并且几种人类 PP2C 的缺陷与癌症、糖尿病、心血管疾病有关 疾病、神经紊乱和压力信号。然而，对于 PP2C 如何 酶活性受到调节，哪些特定蛋白质和过程受 PP2C 控制。在植物中， PP2C.D PPase 通过抑制细胞扩张来抑制器官生长。在某种程度上，这是通过以下方式实现的 质膜 (PM) H+-ATP 酶的关键调节磷酸位点的去磷酸化。成长 激素生长素通过诱导小生长素 Up RNA (SAUR) 基因的表达来刺激细胞扩张，该基因 编码与 PP2C.D PPase 结合以抑制酶活性的新型蛋白质。本次活动的长远目标 该项目旨在彻底了解生长素介导的植物控制的分子机制 成长和发展。更具体地说，本提案中描述的工作将确定监管机构和 SAUR-PP2C.D 信号中枢的下游效应器参与生长素介导的细胞扩增和 将体积变化与不同的细胞过程相结合，以产生协调的生长反应。 磷酸化蛋白质组学研究已经鉴定出超过 140 种蛋白质表现出磷酸化的改变，以响应 生长素。该数据集与受 SAUR 过表达影响的磷蛋白有很大重叠，这意味着 SAUR-PP2C.D 模块作为细胞扩增过程中生长素磷酸化组的主要调节因子。使用 模式植物拟南芥的强大遗传系统，拟议的研究将调查其功能 选择磷蛋白候选物在生长素诱导的生长中的作用及其与 SAUR- 的调节相互作用 PP2C.D 模块。还将对生长素对 PM H+-ATPase 活性的调节进行详细分析。 生长素既通过 SAUR 抑制 PP2C.D 活性来抑制 H+-ATPase 去磷酸化，又刺激 通过 TMK1 和其他激酶（包括 WNK 的直向同源物）促进 ATP 酶磷酸化来激活 和SPAK/OSR 激酶与哺乳动物细胞大小控制有关。所有这些激酶都与一种激酶相互作用 另一个和 PP2C.D PPase，研究将解决激酶和磷酸酶活性如何变化 相互协调、相互监管。这项工作将阐明 PP2C 的功能和调节机制， 识别调节细胞扩张的 PP2C.D 效应子，并阐明生长素如何协调不同的细胞 控制细胞大小的过程。鉴于 PP2C 功能在各个王国之间的守恒性和普遍性 细胞大小控制过程，项目研究结果将产生广泛的影响，包括对人类的影响 发育和疾病。此外，由于人类依赖植物作为食物、纤维和营养物质的来源 药物，拟议的研究将阐明 SAUR-PP2C.D 监管对植物生长的控制 模块并促进操纵植物生长以造福人类健康的新策略。