Tyrosine Kinase Signaling in Nuclear Morphodynamics

真核细胞，包括人类细胞，被分成称为细胞器的隔间，这些细胞器已经进化成执行特定功能的同时保护细胞的其余部分免受潜在有害活动的影响。这种细胞器的划分给细胞在协调细胞活动方面带来了巨大的挑战。为了应对环境的变化或内部的变化，细胞必须重新安排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，以其在保护和控制遗传信息方面的关键功能而闻名。然而，像任何其他细胞器一样，细胞核是高度动态的，它在细胞内的形状和位置经历了显著的变化。这些变化被认为对组织内细胞的正常功能产生了深远的影响，从而对组织的完整性产生了影响。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，如胚胎发育或成年组织修复期间。当细胞不能正确地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学后果。事实上，核结构和定位的缺陷与癌症和退行性肌肉疾病等致命人类疾病的发展相关。然而，我们仍然不知道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，这使得我们很难计算出这一过程在人类疾病中可能是如何解除调控的。 为了接收和传递细胞外和细胞内信号的指令，细胞在包括细胞核在内的所有细胞器中都有复杂的信号装置。信号电路由蛋白质硬件组成，通过可逆的蛋白质修饰传递信号，包括蛋白质磷酸化。蛋白激酶是催化蛋白质磷酸化的酶，充当传递信号的分子开关。我们对信号转导机制的了解大多局限于细胞质膜上最初的信号接收和整合，而对细胞核内的信号转导还不清楚。这个项目的总体目标是了解在细胞核内产生的蛋白质磷酸化如何影响核形状和位置的调节，以及在哪些生理和病理条件下。具体地说，我们将研究一种名为Src的重要酪氨酸激酶的潜在作用，它可以响应各种改变细胞形状的信号而移动到细胞核，以及位于细胞核中的新发现的蛋白质靶标Src。这项基础性工作应该有助于更好地了解癌症和退行性疾病等疾病的基础知识。

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.