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

描述(申请人提供)：在许多人类肿瘤中分别检测到表皮生长因子受体(EGFR)的过度表达和β-连环蛋白的反式激活，并与不良的临床预后相关。我们最近发现，EGFR的激活可诱导糖原合成酶激酶-3？(GSK3？)-典型的途径非依赖性方式。然而，EGFR诱导的信号如何调节核连环蛋白的反式激活，从而促进肿瘤进展仍不清楚。 丙酮酸激酶同工酶M2(PKM2)调节糖酵解的限速最后一步，在肿瘤的发生中起重要作用。除了在细胞代谢中的作用已被广泛研究外，PKM2还通过一种未知的机制促进细胞增殖。 我们的初步数据显示，EGFR的激活导致了PKM2的核转位。此外，核转位的PKM2与β-连环蛋白相互作用，并介导？-连环蛋白调控的基因转录。我们假设，通过与核PKM2相互作用来调节β-连环蛋白在EGFR促进的肿瘤发展中起着重要作用。在特定的目标1中，我们将确定EGF诱导的PKM2核转位的机制。在特定的目标2中，我们将确定核PKM2与β-连环蛋白之间的相互作用是否在EGF诱导的？-连环蛋白反式激活中起重要作用。在特定的目标3中，我们将区分胞质和核的PKM2的功能，并确定PKM2对β-连环蛋白的调节在EGFR促进的肿瘤发展中的作用。我们期望我们的研究将提供重要的和以前未被揭示的机制，通过串扰EGFR和Wnt通路促进肿瘤的发展，这些途径依赖于PKM2的非代谢功能。基于我们的发现，针对EGF诱导的β-连环蛋白调节的治疗策略可能被开发出来，以加强目前基于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.