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

项目摘要 我们认为AXL是一种受体酪氨酸激酶AXL(RTK)，它可以被非配体依赖的受体激活 通过与另一种RTK、MET相互作用的方式，形成异二聚体AXL-MET复合体来发射 一种独特的癌细胞迁移和侵袭信号程序。 MET和Ax1是两个新近鉴定的致癌RTK，参与侵袭性细胞生长和 癌细胞迁移。新的证据表明，Axl或AXL的异常激活和过度表达 MET基因扩增使靶向治疗和常规治疗具有共同的耐药机制 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的共同激活和/或与其他RTK如EGFR或IGF-1R的相遇也被认为是主要的 阻碍了有针对性的癌症治疗。许多RTK的规范激活涉及到一个 特异性配体对其同源受体促进RTK同源二聚化启动特定信号 卡斯卡德。我们最近发现，HGF是MET RTK的天然配体，它能诱导一种 不同的RTK，AXL，通过促进形成MET-AXL异源RTK复合体来触发新的 下游信号级联作用于癌细胞迁移和侵袭。我们的研究结果是关于 Met-Axl异源RTK络合物代表了一种新的、未被表征的激活RTK的机制。 我们建议研究这一新的信号传递过程，为未来的治疗提供新的靶点。 在本应用程序中，我们将研究AXL通过与 MET通过实现以下具体目标来促进癌细胞的运动： 具体目的1.确定同源RTK和异源RTK复合体之间的关系 具体目标2.确定潜在的激活和信号级联的新机制 Met-Axl异源RTK复合体。 具体目的3.确定选择性缺失AXL的p140形式的影响。 由于RTKs的共激活在GBM和许多人类癌症中至关重要，因此阐明 这种新的调控机制可能为预防和治疗提供新的靶点。

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.