Tyrosine Kinase Signaling in Nuclear Morphodynamics

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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.