Identification and Characterization of a Integrin - Notch signaling Axis

描述(由申请人提供)： 细胞外基质、整合素和Notch信号机制在从海绵到人类的多种多细胞生物中都是保守的，在正常情况下对维持细胞内平衡至关重要。相反，在病理条件下，细胞外基质、整合素和Notch信号共同与多种人类病理有关，包括但不限于肿瘤血管生成、生长、侵袭和转移。我们的初步结果发现了一种先前未知的信号机制，该机制通过RGD结合？3和？6整合素将细胞外基质与改变的Notch信号偶联。因此，这一建议的主要假设是，细胞外基质中含有RGD的分子通过连接含有整合素的？3和？6而对Notch信号产生负面影响。这项提议的主要目标是从四个不同的角度和四个相辅相成的具体目标来检验这一假设。在目标1中，我们将剖析整合素3和6抑制Notch信号的机制基础。在目标2中，我们将为协同抑制Notch的整合素和6整合素确定整合素结合伙伴。在目标3中，我们将确定是否所有促血管生成和抗血管生成的细胞外基质蛋白的RGD结构域都具有同样的抑制Notch信号的能力。在目标4中，我们将确定是否整合素3和6抑制了来自所有Notch受体/配体组合的信号，或者是否特定的Notch受体/配体组合被优先抑制。通过解决这四个目标，本提案将剖析一种全新的细胞信号机制的基本参数，该机制将对我们理解与细胞外基质、整合素和Notch信号相关的正常和疾病过程产生广泛影响。通过解决这一信号机制的基本参数，这一提议将为未来的研究奠定基础，这些研究将解决这一机制对癌症和血管生成的生物学意义。 公共卫生相关性： 细胞外基质、整合素和Notch信号共同参与调节正常和病理细胞生理学中令人难以置信的各种事件。根据我们的初步数据，我们假设细胞外基质通过整合素3和6控制Notch信号转导。本文描述的实验将探索这一假设，并在这样做的过程中，将对我们理解细胞外基质、整合素和Notch信号如何合作不仅控制正常细胞生物学，而且控制与癌症等疾病相关的病理细胞生物学产生巨大影响。

DESCRIPTION (provided by applicant): Extracellular matrix, integrins, and Notch signaling mechanism are conserved between a wide variety of multi-cellular creatures from sponges to man and under normal conditions are critical for maintaining cellular homeostasis. Conversely, under pathological conditions, extracellular matrix, integrins, and Notch signaling are collectively associated with a wide variety of human pathologies including but not limited to tumor angiogenesis, growth, invasion, and metastasis. Our preliminary results have discovered a previously unidentified signaling mechanism that couples extracellular matrix to altered Notch signaling via RGD binding ¿3 and ¿6 integrins. Therefore, the main hypothesis of this proposal is that RGD containing molecules in the extracellular matrix negatively impact Notch signaling by ligating ¿3 and ¿6 containing integrins. The main goal of this proposal is to examine this hypothesis from four different angles with four complementary specific aims. In aim 1, we will dissect the mechanistic basis by which ¿3 and ¿6 integrins suppress Notch signaling. In aim 2, we will identify ¿ integrin binding partners for ¿ and ¿6 integrins that cooperate to suppress Notch. In aim 3, we will determine if all RGD domains of pro- and anti-angiogenic extracellular matrix proteins are equally capable of suppressing Notch signaling. In aim 4, we will determine if ¿3 and ¿6 integrins suppress signaling from all Notch receptor/ligand combinations or if specific Notch receptor/ligand combinations are preferentially suppressed. By addressing these four aims, this proposal will dissect the basic parameters of a completely novel cell signaling mechanism that will have a broad impact on our understanding of normal and disease processes that as associated with extracellular matrix, integrins and Notch signaling. By addressing the basic parameters of this signaling mechanism, this proposal will lay the foundation for future research that will address the biological significance of this mechanism to cancer and angiogenesis. PUBLIC HEALTH RELEVANCE: Extracellular matrix, integrins, and Notch signaling are collectively involved in regulating an incredible diversity of events in normal and pathological cell physiology. Based on our preliminary data, we hypothesize that extracellular matrix controls Notch signaling via ¿3 and ¿6 integrins. The experiments described herein will explore this hypothesis and in so doing, will make a tremendous impact on our understanding of how extracellular matrix, integrins, and Notch signaling cooperate to control not only normal cell biology but also pathological cell biology associated with diseases such as cancer.