Mechanisms of FGF Receptor Regulation and Signaling

FGF 受体调节和信号转导机制

• 批准号: 9891850
• 负责人: MOOSA MOHAMMADI
• 金额: $ 60.2万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891850
• 关键词: Academia; Achievement; Address; Adipose tissue; Affinity; Agonist; Antidiabetic Drugs; Binding; Binding Sites; Biology; Blood Circulation; Cardiovascular Diseases; Cells; Charge; Chronic Kidney Failure; Clinical Trials; Complex; Comprehension; Cryoelectron Microscopy; Crystallization; Data; Development; Dimerization; Disease; Drug Industry; Economic Burden; Embryonic Development; Endocrine; Excretory function; Exhibits; FGF21 gene; FGFR2 gene; FGFR4 gene; Family; Family member; Fasting; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; Glucose; Goals; Grant; Heparin; Heparitin Sulfate; Homeostasis; Hormones; Human; Human Development; Kidney; Knowledge; Laboratories; Ligands; Lipids; Lipolysis; Liver; Malignant Neoplasms; Mediating; Medical; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitogens; Molecular; Mutation; NMR Spectroscopy; Negative Staining; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenicity; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiological; Process; Proximal Kidney Tubules; Public Health; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Serum; Signal Transduction; Site; Specificity; Structure; Sulfate; System; Testing; Therapeutic; Tissues; Tyrosine; Tyrosine Kinase Domain; Tyrosine Phosphorylation; Vitamin D; Wasting Syndrome; X-Ray Crystallography; base; bone; cofactor; derepression; design; dimer; driving force; drug candidate; drug discovery; gain of function; gain of function mutation; glucose uptake; human disease; inorganic phosphate; insight; insulin sensitivity; morphogens; novel; novel therapeutics; paracrine; particle; polypeptide; receptor; receptor binding; scaffold; skeletal disorder; small molecule; social; structured data; success; therapeutic target

The mammalian FGF family comprises 18 structurally-related polypeptides, which have traditionally been known as paracrine acting mitogens and morphogens that mediate key processes throughout embryonic development. The discovery that three members of this family act as hormones has transformed the FGF signaling field and sparked major drug discovery activities centered on these ligands in both academia and pharmaceutical industries. FGF21 has been studied as an anti-diabetic drug candidate owing to its glucose- and lipid-lowering action, and various FGF21 agonists are already being tested in clinical trials for use in type II diabetes, obesity, and related metabolic disorders. Antagonists to FGF23, a key regulator of phosphate homeostasis, are being developed as the first causative therapy for patients with renal phosphate wasting disorders to block the action of excess FGF23 in these patients, and are also considered for treating cardiovascular disease in chronic kidney disease. FGFs carry out their diverse functions by binding, dimerizing, and thereby activating the FGF receptor (FGFR) subfamily of RTKs. The classic paracrine FGF ligands require heparin sulfate (HS) as a cofactor for activating FGFRs, whereas the hormone-like FGFs depend on Klotho coreceptors. HS- or Klotho-assisted FGF-FGFR dimerization enables the trans- phosphorylation on cytoplasmic kinase A-loop tyrosines to activate the autoinhibited “catalytically-repressed” FGFR kinases, and therefore is a mandatory step in FGF signal transduction. The tremendous biomedical significance of FGF signaling has been the driving force behind the studies on the structural basis of this signaling system, which my laboratory has been spearheading since inception of this grant in 2000. Building upon the achievements of the previous grant cycles, in this competing renewal we propose three Specific Aims to address imminent knowledge gaps in FGF signaling that will have a significant and persistent impact on FGF/RTK signaling and its therapeutic targeting. Aims I & II will unravel the mechanisms by which Klotho coreceptors assist endocrine FGFs to dimerize and activate their cognate FGFRs, and hence pave the way for the discovery of novel therapeutics for major metabolic diseases, such as type II diabetes, obesity, and chronic kidney disease, which pose some of the biggest threats to public health and worldwide economy. Aim III will exploit a unique gain-of-function mutation in FGFR to solve the longstanding paradox of how unphosphorylated catalytically-repressed RTKs perform the initial A-loop tyrosine transphosphorylation to become activated. Our discovery of an unprecedented “induced fit” asymmetric dimerization of FGFR kinases, which triggers A-loop tyrosine phosphorylation by overcoming an autoinhibitory charge repulsion, will advance our comprehension of signal transduction by majority of RTKs that rely on A-loop tyrosine transphosphorylation as the activating step. This Aim will also provide the details of how this pathogenic mutation hijacks the physiological mechanism underlying A-loop tyrosine phosphorylation to confer gain-of-function on the kinase.

哺乳动物成纤维细胞生长因子家族由18个结构相关的多肽组成，这些多肽传统上是 被称为旁分泌作用的有丝分裂原和形态原，在整个胚胎过程中调节关键过程 发展。这个家族中的三个成员作为荷尔蒙的发现改变了成纤维细胞生长因子 并引发了以这些配体为中心的重大药物发现活动 制药行业。FGF21由于其葡萄糖-21的特性而被研究作为抗糖尿病药物的候选药物。 和降脂作用，各种FGF21激动剂已经在临床试验中用于II型 糖尿病、肥胖症和相关的代谢紊乱。磷酸盐的关键调节因子FGF23的拮抗剂 动态平衡，正在被开发为治疗肾性磷酸盐消耗患者的第一种致病疗法 在这些患者中，阻断过量FGF23作用的紊乱，也被考虑用于治疗 慢性肾脏疾病中的心血管疾病。FGFs通过绑定来执行其不同的功能， 二聚体，从而激活RTK的成纤维细胞生长因子受体(FGFR)亚家族。经典旁分泌成纤维细胞生长因子 配体需要硫酸肝素(HS)作为激活FGFRs的辅因子，而激素样的FGFs 依赖于Klotho辅助受体。HS或Klotho辅助的FGF-FGFR二聚化使反式- 胞浆蛋白激酶A环酪氨酸的磷酸化激活自身抑制的“催化抑制” 因此，FGFR是成纤维细胞生长因子信号转导的必经步骤。巨大的生物医学 成纤维细胞生长因子信号转导的意义一直是这一结构基础研究的驱动力 信号系统，我的实验室自2000年这项拨款开始以来一直在带头。建房 在前几个赠款周期取得成就的基础上，在这次竞争性续期中，我们提出了三个具体目标 解决成纤维细胞生长因子信号方面的迫在眉睫的知识差距，这将对 成纤维细胞生长因子/RTK信号转导及其治疗靶向AIMS I和II将揭开Klotho 辅受体协助内分泌FGFs二聚化并激活其同源FGFRs，从而为 发现治疗主要代谢性疾病的新疗法，如II型糖尿病、肥胖症和慢性 肾脏疾病，这对公共健康和世界经济构成了一些最大的威胁。AIM III将 利用FGFR中独特的功能增益突变来解决长期存在的如何去磷酸化的悖论 被催化抑制的RTK首先执行A-环酪氨酸转磷酸化，然后被激活。我们的 发现一种史无前例的“诱导配合”不对称二聚化FGFR激酶，触发A环 通过克服自身抑制电荷排斥力的酪氨酸磷酸化，将促进我们对 大多数RTK的信号转导依赖于A-环酪氨酸转磷酸作为激活步骤。 这一目标也将提供致病突变如何劫持生理机制的细节。 潜在的A-环酪氨酸磷酸化，赋予该激酶功能增益。

项目成果

CAM therapies among primary care patients using opioid therapy for chronic pain.

• DOI: 10.1186/1472-6882-7-15
• 发表时间: 2007-05-16
• 期刊: BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE
• 作者: Fleming, Sara;Rabago, David P;Mundt, Marlon P;Fleming, Michael F
• 通讯作者: Fleming, Michael F

Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation.

致病性 FGF 受体 3 突变对 a 环酪氨酸磷酸化的结构模拟。

• DOI: 10.1016/j.str.2013.07.017
• 发表时间: 2013-10-08
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Huang, Zhifeng;Chen, Huaibin;Blais, Steven;Neubert, Thomas A.;Li, Xiaokun;Mohammadi, Moosa
• 通讯作者: Mohammadi, Moosa

The FGF family: biology, pathophysiology and therapy.

• DOI: 10.1038/nrd2792
• 发表时间: 2009-03
• 期刊: Nature reviews. Drug discovery

Inhibition of growth hormone signaling by the fasting-induced hormone FGF21.

• DOI: 10.1016/j.cmet.2008.05.006
• 发表时间: 2008-07
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Inagaki, Takeshi;Lin, Vicky Y.;Goetz, Regina;Mohammadi, Moosa;Mangelsdorf, David J.;Kliewer, Steven A.
• 通讯作者: Kliewer, Steven A.

A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.

• DOI: 10.1016/j.str.2019.05.002
• 发表时间: 2019-08
• 期刊: Structure
• 影响因子: 5.7
• 作者: William Marsiglia;Joseph Katigbak;Sijin Zheng;M. Mohammadi;Yingkai Zhang;N. Traaseth