Mechanisms of FGF Receptor Regulation and Signaling

哺乳动物FGF家族包含18种结构相关的多肽，其传统上被认为是 被称为旁分泌作用的有丝分裂原和形态发生素，其介导整个胚胎发育的关键过程， 发展发现这个家族的三个成员作为激素已经改变了FGF 信号领域，并引发了主要的药物发现活动集中在这些配体在学术界和 制药行业。FGF 21由于其葡萄糖-葡萄糖代谢而被研究为抗糖尿病候选药物。 和降脂作用，各种FGF 21激动剂已经在临床试验中测试用于II型糖尿病。 糖尿病、肥胖症和相关代谢紊乱。FGF 23的拮抗剂，磷酸盐的关键调节剂 体内平衡，正在开发作为肾性磷酸盐消耗患者的第一种病因治疗 在这些患者中阻断过量FGF 23的作用，并且也被考虑用于治疗 慢性肾脏病的心血管疾病。FGF通过结合， 二聚化，从而激活RTK的FGF受体（FGFR）亚家族。经典的旁分泌FGF 配体需要硫酸肝素（HS）作为激活FGFR的辅因子，而类肝素FGF 依赖于Klotho辅助受体。HS-或Klotho-辅助的FGF-FGFR二聚化使得反式- 细胞质激酶A环酪氨酸磷酸化以激活自身抑制的“催化抑制的” FGFR激酶，因此是FGF信号转导的必要步骤。巨大的生物医学 FGF信号传导的重要性一直是研究其结构基础的驱动力。 信号系统，我的实验室自2000年获得该资助以来一直在带头研究。建筑 在前几个资助周期取得成就的基础上，在这次竞争性的更新中，我们提出了三个具体目标 解决FGF信号传导中即将出现的知识空白，这将对 FGF/RTK信号传导及其治疗靶向。目标I和II将揭示Klotho 辅助受体协助内分泌FGF二聚化并激活其同源FGFR，并因此为 发现用于主要代谢疾病的新疗法，如II型糖尿病、肥胖症和慢性 肾脏疾病是对公众健康和全球经济构成最大威胁的疾病之一。Aim III将 利用FGFR中独特的功能获得性突变来解决长期存在的矛盾，即非磷酸化 催化抑制的RTK进行初始的A环酪氨酸转磷酸化而被激活。我们 发现FGFR激酶前所未有的“诱导契合”不对称二聚化，其触发A环 酪氨酸磷酸化通过克服自身抑制电荷排斥，将促进我们对 通过依赖于A环酪氨酸转磷酸化作为活化步骤的大多数RTK的信号转导。 本目标还将提供这种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激酶功能获得。

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.