Regulation of nuclear Beta-catenin in EGFR-promoted tumor development.

描述（由申请方提供）：表皮生长因子（EGF）受体（EGFR）的过表达和？-连环蛋白已经在许多人类肿瘤中被单独检测到，并且与不良的临床预后相关。我们最近发现EGFR激活诱导？-糖原合成酶激酶-3中的连环蛋白反式激活？(GSK3?)-规范路径独立的方式。然而，EGFR诱导的信号传导如何调节核？连环蛋白反式激活并由此促进肿瘤进展仍不清楚。 丙酮酸激酶同工酶M2（PKM 2），它调节糖酵解的限速最后一步，是肿瘤发生的工具。除了其在细胞代谢中的充分研究的作用，PKM 2通过未知的机制促进细胞增殖。 我们的初步数据表明，EGFR的激活导致PKM 2核转位。此外，核转位PKM 2与？- catenin和mediates？-连环蛋白调控的基因转录。我们假设？-连环蛋白通过与核PKM 2相互作用在EGFR促进的肿瘤发展中起着重要作用。在具体目标1中，我们将确定EGF诱导PKM 2核转位的机制。在具体目标2中，我们将确定核PKM 2与？连环蛋白是EGF诱导的？连环蛋白反式激活在具体目标3中，我们将区分胞浆和核PKM 2的功能，并确定？EGFR促进的肿瘤发展中PKM 2对连环蛋白的调节我们希望我们提出的研究将提供重要的和以前未发现的EGFR促进肿瘤发展的机制，通过crosstalking EGFR与Wnt途径，这是依赖于PKM 2的非代谢功能。基于我们的研究结果，针对EGF诱导的？可以开发连环蛋白调节以增强当前基于EGFR的癌症治疗。

DESCRIPTION (provided by applicant): Overexpression of epidermal growth factor (EGF) receptor (EGFR) and transactivation of ?-catenin have been detected separately in many human tumors and correlate with a poor clinical prognosis. We recently revealed that EGFR activation induces ?-catenin transactivation in a glycogen synthase kinase-3? (GSK3?)-canonical pathway-independent manner. However, how EGFR-induced signaling regulates nuclear ?-catenin transactivation and thereby promotes tumor progression remains unclear. Pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis, is instrumental for tumorgenesis. In addition to its well-studied role in cell metabolism, PKM2 promotes cell proliferation though an unknown mechanism. Our preliminary data showed that activation of EGFR results in PKM2 nuclear translocation. In addition, nuclear translocated PKM2 interacts with ?-catenin and mediates ?-catenin-regulated gene transcription. We hypothesize that regulation of ?-catenin by interacting with nuclear PKM2 plays an instrumental role in EGFR-promoted tumor development. In Specific Aim 1, we will determine the mechanisms underlying EGF-induced PKM2 nuclear translocation. In Specific Aim 2, we will determine whether the interaction between nuclear PKM2 to ?-catenin is essential for EGF-induced ?-catenin transactivation. In Specific Aim 3, we will differentiate the functions of cytosolic and nuclear PKM2 and determine the role of ?-catenin regulation by PKM2 in EGFR-promoted tumor development. We expect that our proposed research will provide important and previously unrevealed mechanisms of EGFR-promoted tumor development via crosstalking EGFR with Wnt pathways, which are dependent on nonmetabolic functions of PKM2. Building on our findings, therapy strategies targeting EGF-induced ?-catenin regulation may be developed to enhance current EGFR-based cancer therapies.