Non-canonical signal pathway for Crk in breast cancer
乳腺癌中 Crk 的非经典信号通路
基本信息
- 批准号:8701004
- 负责人:
- 金额:$ 27.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-12 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAdenocarcinomaAffinityApoptoticBehaviorBindingBinding SitesBiological AssayBiological ProcessBreastBreast Cancer CellCancer PatientCancer PrognosisCancer cell lineCell physiologyCell-Cell AdhesionCellsChickensClinical ResearchDataDetectionDevelopmentEmbryoEpidermal Growth Factor ReceptorEukaryotic CellFatty acid glycerol estersFibroblastsGenerationsGlioblastomaGuanine Nucleotide Exchange FactorsHumanImmigrationInterventionLungMalignant - descriptorMalignant NeoplasmsMediatingModelingN-terminalNamesNeoplasm MetastasisOvarianPTB DomainPathway interactionsPhosphorylationPhosphorylation SitePhosphotransferasesPlayPositive Lymph NodePredispositionPrognostic MarkerPropertyProtein BindingProtein Tyrosine KinaseProtein-Kinase OncogenesProteinsReceptor Protein-Tyrosine KinasesRecruitment ActivityRegulationResearchRoleSH3 DomainsSignal PathwaySignal TransductionSignal Transduction PathwaySiteSmall Interfering RNAStomachStomach CarcinomaStructureTestingTherapeuticTranslatingTyrosineTyrosine PhosphorylationTyrosine Phosphorylation SiteTyrosine-Kinase Oncogenesbasecancer cellcell behaviorcell growthcell motilitycell transformationcis trans isomerizationclinically significantin vivoinnovationmalignant breast neoplasmmalignant phenotypemembermouse modelnoveloverexpressionpolyclonal antibodyprotein complexprotein expressionprotein functionprotein protein interactionproto-oncogene protein c-crkreceptorsarcomascreeningsynovial sarcomatherapeutic targettumortumor progression
项目摘要
DESCRIPTION (provided by applicant): The Src Homology 2 (SH2) and Src Homology 3 (SH3) domain-containing protein Crk is the prototypical member of a class of adaptor proteins that play essential roles in signaling downstream of tyrosine kinases. By promoting the assembly of protein complexes mediated by the SH2 and SH3 domains, evidence accumulated over the past two decades has elucidated a canonical pathway for Crk signaling whereby the SH2 domain binds tyrosine phosphorylated proteins and the N-terminal SH3 domain (SH3N) binds guanine-nucleotide exchange factors that activate Rac1, Rap1, and Ras. The clinical significance of Crk in human cancer has been enumerated in recent years, as Crk is frequently over-expressed in several different cancers, including breast, ovarian, gastric, lung, glioblastoma, and sarcomas and siRNA-mediated knockdown of Crk reverses the malignant and metastatic features of these cancers. These observations have led to a new urgency to understand the mechanisms by which Crk promotes malignant transformation in the hope that new information can be exploited to develop therapeutics, particularly for tumors with a predisposition towards invasion and metastasis.
In this application we have identified a new signaling paradigm for Crk by the identification of two previously uncharacterized tyrosine phosphorylation sites located within the carboxyl-terminal SH3 (SH3C) domain, an atypical SH3 domain that has no clear biological function. Tyr251 is located in the highly conserved RT-loop of the Crk SH3C while Tyr239 is located at the boundary of the linker and SH3C and comprises a region of Crk implicated in the negative regulation and auto-clamping of the SH3C to the SH3N. The central hypothesis of this application is that Crk, in addition to its canonical role as an adaptor protein, has an unconventional role in signal transduction through phosphorylation of Tyr251 and Tyr239, that define new binding sites allowing recruitment of SH2 and/or PTB domain containing proteins. The recruitment of these proteins may initiate post-phosphorylation-dependent signaling pathways relevant to cell transformation. Both sites are tyrosine phosphorylated by EGFR and ErbB2 receptors suggesting this research is directly relevant to signaling in cancer cells that have overexpressed or activated receptor tyrosine kinases oncogenes. In recent years, an emerging body of evidence suggests that Crk proteins are overexpressed in human tumors and the expression levels correlate with aggressive and malignant behavior of cancer cells. These properties of Crk proteins make them potential cancer prognosis markers and therapeutic targets.
描述(由申请人提供):包含 Src 同源 2 (SH2) 和 Src 同源 3 (SH3) 结构域的蛋白 Crk 是一类接头蛋白的典型成员,在酪氨酸激酶下游信号传导中发挥重要作用。通过促进 SH2 和 SH3 结构域介导的蛋白质复合物的组装,过去二十年积累的证据阐明了 Crk 信号传导的经典途径,其中 SH2 结构域结合酪氨酸磷酸化蛋白,N 端 SH3 结构域 (SH3N) 结合鸟嘌呤-激活 Rac1、Rap1 和 Ras 的核苷酸交换因子。近年来,Crk 在人类癌症中的临床意义已被列举,因为 Crk 在几种不同的癌症中经常过表达,包括乳腺癌、卵巢癌、胃癌、肺癌、胶质母细胞瘤和肉瘤,并且 siRNA 介导的 Crk 敲低可逆转恶性癌症。以及这些癌症的转移特征。这些观察结果使得了解 Crk 促进恶性转化的机制变得更加紧迫,希望能够利用新信息来开发治疗方法,特别是针对具有侵袭和转移倾向的肿瘤。
在本申请中,我们通过鉴定位于羧基末端 SH3 (SH3C) 结构域(一种没有明确生物学功能的非典型 SH3 结构域)内的两个先前未表征的酪氨酸磷酸化位点,确定了 Crk 的新信号传导范式。 Tyr251 位于 Crk SH3C 的高度保守 RT 环中,而 Tyr239 位于连接子和 SH3C 的边界处,并包含与 SH3C 对 SH3N 的负调节和自动钳位有关的 Crk 区域。本申请的中心假设是,Crk 除了作为衔接蛋白的典型作用外,还通过 Tyr251 和 Tyr239 的磷酸化在信号转导中发挥非常规作用,这定义了新的结合位点,允许招募含有 SH2 和/或 PTB 结构域的蛋白质。这些蛋白质的募集可能启动与细胞转化相关的磷酸化后依赖性信号通路。这两个位点均被 EGFR 和 ErbB2 受体酪氨酸磷酸化,表明这项研究与过度表达或激活受体酪氨酸激酶癌基因的癌细胞中的信号传导直接相关。近年来,越来越多的证据表明,Crk 蛋白在人类肿瘤中过度表达,并且表达水平与癌细胞的侵袭性和恶性行为相关。 Crk 蛋白的这些特性使其成为潜在的癌症预后标志物和治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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RAYMOND B BIRGE其他文献
RAYMOND B BIRGE的其他文献
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Non-canonical signal pathway for Crk in breast cancer
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