Understanding Signaling by Non-Canonical Receptor Tyrosine Kinases

了解非典型受体酪氨酸激酶的信号传导

• 批准号: 10406442
• 负责人: Mark A Lemmon
• 金额: $ 77.05万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406442
• 关键词: Acylation; Binding; Bone Diseases; Complex; Congenital Abnormality; Crystallography; Defect; Dependence; Dimerization; Disease; Extracellular Structure; Human; Insulin Receptor; Knowledge; Ligand Binding; Ligands; Malignant Neoplasms; Methods; Modeling; Molecular Conformation; Neurodevelopmental Disorder; Phosphotransferases; Play; Property; Protein Tyrosine Kinase; Proteins; ROR1 gene; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research; Resolution; Role; Signal Transduction; Signaling Molecule; Subcellular structure; Testing; Therapeutic; Tyrosine; Tyrosine Kinase Domain; WNT Signaling Pathway; beta catenin; conformational conversion; extracellular; human disease; insight; kinase inhibitor; member; novel therapeutic intervention; novel therapeutics; receptor; recruit; small molecule; therapeutic target; wound healing

The research proposed in this MIRA renewal application seeks to understand mechanisms of transmembrane signaling by members of the receptor tyrosine kinase (RTK) superfamily – and other receptor-like kinases – that do not fit the ‘rules’ that explain most RTKs. Non-canonical receptors in this group play important roles in human disease – from neurodevelopmental disorders, to bone diseases, cancers, and congenital malformations. The traditional model for RTK signaling involves ligand-induced receptor dimerization, which promotes tyrosine autophosphorylation of the receptor and recruitment of downstream signaling molecules. As we understand more about the 58 human RTKs, it has become clear that this mechanism only applies to about half of them. For example, 10% of human RTKs are linked to WNT signaling, and must function differently because their intracellular regions often have only catalytically inactive ‘pseudokinase’ domains. Still other RTKs (such as ALK) have unique extracellular regions for which ligand binding and receptor regulation are poorly understood. We have made significant progress in understanding extracellular and intracellular structures of WNT-regulated pseudokinase RTKs. Their extracellular WNT-binding modules differ significantly from their counterparts in proteins involved in ‘canonical’ WNT signaling, in ways that suggest well-defined hypotheses for how these RTKs might participate as co-receptors with Frizzled receptors in b-catenin independent WNT signaling. The intracellular pseudokinase domains of the RTKs structurally resemble the insulin receptor kinase in its ‘inactive’ conformation, and analysis of their structural dynamics suggests that they can undergo the same ‘inactive-like’ to ‘active-like’ conformational transitions seen for normal tyrosine kinase domains. Indeed, we have found that these transitions can be promoted by small molecule kinase inhibitor-like molecules, despite the fact that the isolated pseudokinase domains do not bind ATP. In the next 5-10 years of this project, we propose to test hypotheses for WNT-induced assembly of receptor complexes that incorporate pseudokinase RTKs, elucidate their specific WNT dependence and reliance on WNT acylation, gain high resolution structural views through crystallography and EM, and analyze their signaling properties. We will test hypotheses for how the pseudokinase domains contribute to signaling – either by acquiring kinase activity or by functioning as allosterically switchable interaction platforms, with precedents in other pseudokinases and in catalytically active kinases such as Aurora A. In parallel with these efforts, we will investigate new opportunities for therapeutic targeting of pseudokinase RTKs such as PTK7, ROR1, ROR2, and RYK, which have all been implicated in numerous diseases. Together, these studies will provide important new insight into signaling by receptors that do not fit normal paradigms for RTKs or WNT receptors. The new lessons should also be applicable to other classes of receptor-like kinases implicated in disease, opening new avenues for potential therapeutic inhibition.

在此MIRA更新应用中提出的研究旨在了解跨膜的机制 受体酪氨酸激酶（RTK）超家族和其他受体样激酶的信号传导 这不符合大多数RTK的解释。 人类疾病 - 从神经发育障碍到骨骼疾病，癌症和先天性 畸形。 促进受体的酪氨酸自噬和下游信号分子的募集 我们对58个人类RTK的了解更多，很明显，这种机制仅适用于大约 例如，一半 因为他们的cacellar地区通常只有催化的“伪动酶”领域。 RTK（例如ALK）具有独特的外胞外区域，配体结合和受体调节是 理解很差。 WNT调制的假酶RTK的结构。 从参与“规范” Wnt信号传导的蛋白质的对应物中，以明确的方式表明 假设这些可能如何作为与B-catenin中的卷曲受体共同受体参与的假设 独立的Wnt信号传导。 胰岛素受体激酶在其“它”同置以及对其结构动力学的分析中表明， 他们可以经历相同的“不活跃”以“形态过渡”所看到的正式酪氨酸 激酶结构域。 抑制剂样分子，尽管分离的假酶结构域在下一个中不结合ATP。 在该项目的5 - 10年中，我们建议测试Wnt诱导的受体复合物组装的假设 结合了假激酶RTK，阐明了其特定的Wnt依赖性和对Wnt Achlation的依赖， 通过晶体学和EM获得高分辨率的结构视图，并分析其信号传导特性。 我们将测试假酶域的假设有助于信号传导 - 通过获取激酶 活动或通过作为变构可切换的交互平台发挥作用，在其他方面具有先例 假基因基和催化活性激酶（例如Aurora A）与这些启示并联，我们将 研究新的开放率，用于对Pseudokinase RTK的治疗靶向，例如PTK7，ROR1，ROR2，ROR2，ROR2， RYK都与许多疾病有关。 通过受体对RTK或WNT受体的正常范式不适合正常范式的受体信号的新见解 课程也适用于其他类似于疾病的受体样激酶，开放了新的 潜在的治疗性入口的途径。