Tyrosine Kinase Signaling in Nuclear Morphodynamics

核形态动力学中的酪氨酸激酶信号转导

• 批准号: RGPIN-2016-05849
• 负责人: Lavoie, Josée
• 金额: $ 2.26万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=656822
• 关键词: Tyrosine; Kinase; Signaling; Nuclear; Morphodynamics

Eukaryotic cells, including human cells, are divided into compartments called organelles that have evolved to perform specialized functions while protecting the rest of the cell from potentially harmful activities. This partition into organelles presents cells with big challenges in terms of coordination of cellular activities. In response to changes in the environment or to internal alterations, cells must rearrange the structure and positioning of their organelles in a manner that is coordinated with changes of their overall shape. The nucleus, the biggest organelle of a cell, is well known for its crucial function in protecting and controlling the genetic information. Like any other organelles, however, the nucleus is highly dynamic and undergoes remarkable changes in its shape and position within a cell. Such changes are believed to have profound impacts on the proper functioning of cells within tissues, hence on tissue integrity. These so-called nuclear morphodynamics enable cells to adapt to changing conditions and to exhibit an adequate behavior during key processes such as during embryonic development or during tissue repair in adult. When cells fail to correctly control the shape and position of their nucleus, this can have disastrous biological consequences. Indeed, defects in nuclear structure and positioning are correlated with the development of fatal human diseases like cancer and degenerative muscle diseases. However, we still do not understand how a cell is instructed, at the molecular level, to rearrange the structure and position of the nucleus, making it difficult to figure how this process might be deregulated in human diseases. ******To receive and relay instructions by extra- and intracellular signaling, cells possess sophisticated signaling devices in all organelles including the nucleus. The signaling circuits are composed of protein hardware that conveys signals through reversible protein modifications, including protein phosphorylation. Protein kinases, the enzymes that catalyze protein phosphorylation, act as molecular switches to transduce signals. Most of our knowledge regarding signaling mechanisms is limited to the initial signal reception and integration at the plasma membrane and signaling within the nucleus is not understood. The general objective of this program is to understand how protein phosphorylation generated within the nucleus can impact on the regulation of nuclear shape and positioning, and under which physiological and pathological conditions. Specifically, we will investigate a potential role for an important tyrosine kinase called Src, which can move to the nucleus in response to a variety of signals that alter the shape of a cell, and for a newly identified protein target of Src that resides in the nucleus. This fundamental work should contribute to a better foundation knowledge of diseases like cancer and degenerative diseases.**

真核细胞，包括人类细胞，被分成称为细胞器的隔室，这些隔室已经进化到执行专门的功能，同时保护细胞的其余部分免受潜在的有害活动的影响。细胞器的这种划分在细胞活动的协调方面给细胞带来了巨大的挑战。为了应对环境的变化或内部的变化，细胞必须重新排列其细胞器的结构和位置，以与其整体形状的变化相协调。细胞核是细胞中最大的细胞器，在保护和控制遗传信息方面起着至关重要的作用。然而，像任何其他细胞器一样，细胞核是高度动态的，在细胞内的形状和位置都会发生显着变化。这种变化被认为对组织内细胞的正常功能具有深远的影响，因此对组织完整性具有深远的影响。这些所谓的核形态动力学使细胞能够适应不断变化的条件，并在关键过程中表现出适当的行为，例如在胚胎发育期间或在成人组织修复期间。当细胞不能正确控制其细胞核的形状和位置时，这可能会产生灾难性的生物后果。事实上，核结构和定位的缺陷与致命的人类疾病如癌症和退行性肌肉疾病的发展相关。然而，我们仍然不明白细胞是如何在分子水平上被指示重新排列细胞核的结构和位置的，这使得我们很难弄清楚这个过程在人类疾病中是如何被解除管制的。****** 为了通过细胞外和细胞内信号接收和传递指令，细胞在包括细胞核在内的所有细胞器中都拥有复杂的信号装置。信号电路由蛋白质硬件组成，通过可逆的蛋白质修饰（包括蛋白质磷酸化）传递信号。蛋白激酶是催化蛋白质磷酸化的酶，它充当着去磷酸化信号的分子开关。我们对信号传导机制的了解大多局限于最初的信号接收和整合在质膜上，而对核内的信号传导还不了解。该计划的总体目标是了解细胞核内产生的蛋白质磷酸化如何影响细胞核形状和定位的调节，以及在何种生理和病理条件下。具体来说，我们将研究一种重要的酪氨酸激酶Src的潜在作用，它可以移动到细胞核中，以响应改变细胞形状的各种信号，并为一个新发现的蛋白质靶Src驻留在细胞核中。这项基础性工作应有助于更好地了解癌症和退行性疾病等疾病的基础知识。