Regulation of nuclear dynamics by tyrosine kinase signaling

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Each eukaryotic cell, including human cells, is divided into compartments called organelles. These organelles perform specialized functions and protect cells from harmful conditions. However, organelle partitioning presents additional challenges for cells, notably for coordinating cellular activities that dictate specific cell behaviors, such as cell motility and cell division. Moreover, cells need to integrate a variety of signals from the surrounding tissue microenvironment and relay these signals to all organelles. To receive and relay instructions by extra- and intracellular signaling, cells possess sophisticated signaling circuits. These signaling circuits are composed of a protein hardware that conveys signals through reversible protein modifications, including protein phosphorylation. All cellular organelles, including the nucleus, possess their own signaling devices to generate and propagate specific signals. Unfortunately, our understanding of nuclear signaling devices is still limited at both the molecular and functional levels. To maintain tissue integrity, cells must adapt their behaviors to microenvironmental stress including physical constraints in crowded tissues. To achieve this, cells need to rearrange the shape and physical properties of their nucleus. Indeed, the nucleus, which protects genetic material, is the largest and stiffest cell organelle. While dynamic changes in nuclear shape are essential to dictate appropriate cellular behaviors, they can also damage genetic material. Therefore, changes in nuclear shape can either be beneficial or detrimental for cells. How the resulting consequences are determined at the molecular level remains unknown. The general goal of this research program is to understand how cells adapt their nucleus' shape and resilience in response to microenvironmental stress. In the next five years, we will dissect a new signaling pathway that modifies the nucleus' ability to withstand physical constraints, at molecular and functional levels. This pathway involves the phosphorylation of a nuclear protein, Ash2L, by a key component of signaling circuits, Src. Using genetically engineered cell models and innovative bioengineered devices, we will pursue two specific aims: 1) Delineate Ash2L-linked mechanisms of nuclear resilience, by studying nuclear structure organization, nuclear rigidity, and nuclear envelope repair; 2) Assess the regulation of Src-Ash2L pathway by physical constraints and its role in cellular adaptations, by combining live-cell imaging and biochemical analyses of protein modifications. This research program will increase our understanding of functional relationships between cells and the microenvironment that critically impact tissue integrity. It will also generate fundamental knowledge of wide relevance for both life sciences and molecular and cellular engineering.