Novel Regulation of the Activation and Assembly of the Heterimeric Receptor Tyrosine Kinase Complexes for Cell Signaling

细胞信号转导异聚受体酪氨酸激酶复合物的激活和组装的新调控

• 批准号: 10046499
• 负责人: HONG SUN
• 金额: $ 43.72万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046499
• 关键词: Binding; Biological Assay; Biomedical Research; Breast Carcinoma; Cancer Cell Growth; Cells; Characteristics; Chemicals; Complex; DOCK1 protein; Data; Disseminated Malignant Neoplasm; Environment; Epidermal Growth Factor Receptor; Extracellular Domain; Future; Gene Amplification; Glioblastoma; Grant; Guanidines; Guanine Nucleotide Exchange Factors; Homo; Homodimerization; Human; Institution; Lead; Ligand Binding; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular Conformation; Monomeric GTP-Binding Proteins; Nucleotides; Oncogenic; Output; Phosphorylation; Phosphotransferases; Prevention; Process; Protein Isoforms; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Sedimentation process; Signal Transduction; Signaling Molecule; Structure; Sucrose; Therapeutic; Tyrosine; axl receptor tyrosine kinase; base; cancer cell; cancer invasiveness; cancer therapy; cell growth; cell motility; conventional therapy; crosslink; design; dimer; glycosylation; lung Carcinoma; methionylmethionine; monomer; novel; overexpression; programs; receptor; recruit; resistance mechanism; targeted cancer therapy; targeted treatment; undergraduate student

Project Summary We propose that AXL, a receptor tyrosine kinase AXL (RTK), can be activated by ligand-independent manner through interaction with another RTK, MET, and form a heterodimeric AXL-MET complex to launch a unique signaling program for cancer cell migration and invasion. MET and AXL are two recently characterized oncogenic RTKs implicated in invasive cell growth and cancer cell migration. Emerging evidence indicates that aberrant activation and overexpression of AXL or gene amplification of MET confer a common resistance mechanism to targeted and conventional therapies in aggressive and metastatic cancers including glioblatoma multiforme (GBM), breast and lung carcinomas. Co-activation of AXL and/or MET with other RTKs such as EGFR or IGF-1R is also recognized as a major hindrance to targeted cancer therapies. The canonical activation of many RTKs involves the binding of a specific ligand to its cognate receptor to promote RTK homo-dimerization to launch a specific signaling cascade. We have recently found that HGF, a natural ligand for MET RTK, induces the activation of a different RTK, AXL, by promoting the formation of MET-AXL hetero-RTK complexes to trigger a novel downstream signaling cascade for cancer cell migration and invasion. Our findings on the formation of MET-AXL hetero-RTK complexes represent a novel and uncharacterized mechanism for activating RTKs. We propose to investigate this novel signaling process that present new targets for future therapies In this application, we will investigate the mechanism by which AXL is activated through interaction with MET to promote cancer cell motility, by conducting the following specific aims: Specific Aim 1. To determine the relationship between homo-RTK and hetero-RTK complexes Specific Aim 2. To identify the novel mechanism underlying the activation and signaling cascade of the MET-AXL hetero-RTK complex. Specific Aim 3. To determine the effects of selective depletion of the p140 form of AXL. As co-activation of RTKs is critically important in GBM and in a multitude of human cancers, elucidation of this new regulatory mechanism may provide novel targets for prevention and therapeutic treatment.

项目摘要 我们认为AXL是一种受体酪氨酸激酶AXL（RTK），可以被配体非依赖性激活。 通过与另一种RTK，MET相互作用的方式，并形成异二聚体AXL-MET复合物来发射 一种独特的癌细胞迁移和侵袭的信号程序。 MET和AXL是两种最近表征的涉及侵袭性细胞生长的致癌RTK， 癌细胞迁移新出现的证据表明，AXL的异常激活和过度表达或 MET的基因扩增赋予靶向和常规治疗共同的耐药机制 在侵袭性和转移性癌症中，包括多形性胶质母细胞瘤（GBM）、乳腺癌和肺癌。 AXL和/或MET与其他RTK如EGFR或IGF-1 R的共活化也被认为是主要的免疫调节因子。 对靶向癌症治疗的阻碍。许多RTK的典型激活涉及一种 特异性配体与其同源受体结合，促进RTK同源二聚化，从而启动特异性信号传导 级联。我们最近发现，肝细胞生长因子，一种天然配体的MET RTK，诱导激活的一个细胞因子。 不同的RTK，AXL，通过促进MET-AXL异源RTK复合物的形成来引发新的 癌细胞迁移和侵袭的下游信号级联。我们发现， MET-AXL hetero-RTK复合物代表了一种新的和未表征的激活RTK的机制。 我们建议研究这种新的信号传导过程，为未来的治疗提供新的靶点 在本申请中，我们将研究AXL通过与以下物质相互作用而被激活的机制： MET通过以下具体目标促进癌细胞运动： 具体目标1.确定同源RTK和异源RTK复合物之间的关系 具体目标2。为了确定潜在的激活和信号级联的新机制， MET-AXL异源RTK复合物。 具体目标3。确定选择性耗竭p140形式AXL的影响。 由于RTK的共活化在GBM和多种人类癌症中至关重要，因此阐明RTK的共活化在GBM和多种人类癌症中的作用。 这种新的调节机制可能为预防和治疗提供新的靶点。