TGF-beta-induced non-Smad signaling events and cancer cell behavior

TGF-β诱导的非Smad信号传导事件和癌细胞行为

• 批准号: 7565384
• 负责人: RIK M DERYNCK
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565384
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adhesions; Affect; Attention; Behavior; Biochemical; Carcinoma; Cell Shape; Cell Size; Cell physiology; Cells; Cessation of life; Complement; Development; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Gene Expression; Genes; Genetic Transcription; Growth; Immune; Invaded; Investigation; Knowledge; Lead; MAP Kinase Gene; MAP Kinase Signaling Pathways; MAPK Signaling Pathway Pathway; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Mitogen-Activated Protein Kinases; Molecular; Neoplasm Metastasis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Production; Protein Biosynthesis; Proteins; Recruitment Activity; Reporting; Research; Role; Signal Pathway; Signal Transduction; Specificity; Stromal Cells; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Translations; autocrine; base; cancer cell; cancer initiation; cancer therapy; cell behavior; cell motility; epithelial to mesenchymal transition; insight; migration; neoplastic cell; novel; programs; public health relevance; receptor; response; tumor; tumor progression; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Transforming growth factor-¿ (TGF-¿) plays a critical role in cancer initiation and progression. Carcinoma cells often have shown enhanced TGF-¿ production and activation, resulting in autocrine effects on cell physiology and behavior. Among these, a lot of attention has focused on TGF-¿'s ability to induce an epithelial to mesenchymal transition (EMT) that results in de-adhesion, increased motility and invasion. The roles of TGF-¿ in cancer cell behavior, tumor microenvironment and cancer progression are subject of extensive investigation, but the respective roles of the underlying TGF-¿-activated signaling pathways in cancer cell behavior are less understood. Most studies in this context address the roles of TGF-¿-activated Smads, which serve as transcription (co)factors to regulate gene expression. Recent studies, including some from this lab, have characterized non-Smad signaling pathways that are directly activated in response to TGF-¿. These may explain non-transcription responses to TGF-¿ such as migration, changes in cell shape and protein translation, yet may also affect the activities of the Smads. The functions of the non-Smad signaling events in the TGF-¿-directed effects on cancer cell behavior and cancer progression are essentially unknown. We recently reported that, in TGF-¿-induced epithelia EMT, TGF-¿ activates the PI3-kinase-Akt-TOR pathway, resulting in increased protein synthesis and cell size, and that this pathway mediates the increased motility and invasion of cells that undergo TGF-¿-induced EMT. We also reported that, in response to TGF-¿, ShcA is recruited to the type I TGF-¿ receptor T¿RI and phosphorylated on Ser and Tyr, in turn resulting in activation of Erk MAP kinase. Our observation that T¿RI is a dual specificity kinase explains ShcA phosphorylation on Ser and Tyr, whereas T¿RI phosphorylation on Tyr in response to TGF-¿ may provide the biochemical basis for activation of both the PI3K-Akt-TOR and the Shc-Erk MAPK pathways by TGF-¿. Finally, we discovered that phosphorylation of T¿RI in response to TGF-¿ induces T¿RI sumoylation. T¿RI sumoylation in turn regulates TGF-¿-signaling dependent invasion of cancer cells. We propose to further characterize the mechanisms of these signaling events at the molecular level and to use this knowledge to address their roles in cancer cell behavior and cancer progression. Aim 1 will focus on how TGF-¿ activates the PI3K-Akt-TOR pathway and on the role of this component of TGF-¿ signaling in cell invasion and cancer progression. Aim 2 will study the role of TGF-¿-activated ShcA-Erk MAP kinase signaling in EMT, invasion and cancer progression. Aim 3 proposes to better characterize the sumoylation of T¿RI and to understand its role in the TGF-¿ response and cancer progression. Our enthusiasm for this program is driven not only by its inherent scientific importance, but also by its translational potential. PUBLIC HEALTH RELEVANCE: The progression of cancer leading to death is in most cases not the result of the first tumor growing, but rather because that tumor starts invading other tissues and disseminating throughout the body to give rise to additional tumors, a process called metastasis. Cancer invasion and metastasis are driven by a protein called TGF-¿, which is made by the tumor cells themselves and instructs them to undergo the changes that lead to invasion and metastasis. Recently, novel signaling pathways were found that are activated by TGF-¿ and complement the previously studied one that received all attention. The proposed research aims at better understanding the molecular basis of these additional pathways and their roles in cancer cell behavior, cancer progression and metastasis. This knowledge is likely to provide new and more selective avenues than hitherto possible to block the invasive and metastatic behavior of cancers.

描述（由应用程序提供）：转化生长因子 - （TGF- - ）在癌症的开始和进展中起关键作用。癌细胞经常显示出增强的TGF-产生和激活，从而对细胞生理和行为产生自分泌作用。其中，很多关注都集中在TGF- - 诱导上皮过渡（EMT）的能力，从而导致粘附，增加运动性和侵袭。 TGF-在癌细胞行为，肿瘤微环境和癌症进展中的作用是广泛研究的主题，但是在癌细胞行为中，基本的TGF-activiv-activectivectivectivectivectivectivectivectient途径的作用较少。在这种情况下，大多数研究都涉及TGF-激活的SMAD的作用，这些SMAD是转录（CO）调节基因表达的因素。最近的研究，包括来自该实验室的一些研究，表征了非SMAD信号通路，这些途径直接响应于TGF- - 。这些可以解释对TGF-€的非转录反应，例如迁移，细胞形状的变化和蛋白质翻译，但也可能影响SMAD的活性。非SMAD信号事件在TGF-指导对癌细胞行为和癌症进展的影响中的功能本质上是未知的。我们最近报道说，在TGF-¿诱导的上皮EMT中，TGF- - 激活了PI3-激酶-akt-tor途径，从而导致蛋白质的合成和细胞大小增加，并且该途径介导了经历TGF-诱导的EMT的细胞的运动性和侵袭增加。我们还报道说，为了响应TGF- - ，SHCA被募集到I型TGF-€受体T型RI中并在Ser和Tyr上磷酸化，进而导致ERK MAP激酶的激活。我们的观察结果是，t？ri是一种双重特异性激酶，解释了SER和Tyr上的SHCA磷酸化，而Tyr响应TGF-€的TY RI磷酸化可能会为pI3K-AKT-TOR和TGF-shc-erk mapk Pathways tgf-tgf-¿的PI3K-AKT-TOR和SHC-ERK MAPK PATH激活生化基础。最后，我们发现T ri对TGF-€的磷酸化诱导了t¿ri sumoylation。 t¿risumoylation反过来调节癌细胞的依赖性侵袭。我们建议进一步表征分子水平上这些信号事件的机制，并利用这些知识来解决它们在癌细胞行为和癌症进展中的作用。 AIM 1将重点介绍TGF-如何激活PI3K-AKT-TOR途径以及TGF- - 信号在细胞侵袭和癌症进展中的作用。 AIM 2将研究TGF-激活的SHCA-ERK MAP激酶信号在EMT，侵袭和癌症进展中的作用。目标3提案以更好地表征t¿ri的概念并理解其在TGF- - 反应和癌症进展中的作用。我们对该程序的驱动不仅是由于其固有的科学重要性所驱动的，而且还取决于其翻译潜力。公共卫生相关性：在大多数情况下，导致死亡的癌症的进展不是首次肿瘤生长的结果，而是因为该肿瘤开始侵入其他时间并在整个身体中传播以引起其他肿瘤，这一过程称为转移。癌症的侵袭和转移是由一种称为TGF- - 的蛋白质驱动的，该蛋白质由肿瘤细胞本身制造，并指示他们经历导致侵袭和转移的变化。最近，发现新的信号通路被TGF- - 激活并补充了先前研究的人们的注意。拟议的研究旨在更好地了解这些额外途径的分子基础及其在癌细胞行为，癌症进展和转移中的作用。与迄今为止阻止癌症的侵入性和转移行为相比，这些知识可能会提供新的和更多的选择性途径。