Chapter 2: On the Molecular Basis of Cellular Mechanobiology

The tight regulation of cell function in vivo requires the integration of biological and mechanical signals, as evoked by the surrounding extracellular matrix (ECM) or by neighboring cells. In this chapter, we describe the current understanding of the intracellular molecular processes through which physical cues generated at the ECM are turned into a biological response. These processes, which are the subject of intense investigation in the interdisciplinary field of mechanobiology, are needed for cellular timely adaptation to the continuous dynamic modifications of the microenvironment. By starting from the most recent findings in the field, we conceive a centripetal model of mechanotransduction whereby macromolecular complexes sitting at the interphase between ECM and the cell cytoplasm serve as the primary hub for the cell to perceive mechanical stress. Following the prompt rearrangement of the cellular membrane and focal adhesions, the inward transmission of the mechanical signal is ensured by the dynamic fine-tuning of cytoskeleton tension and the linker of nucleoskeleton and cytoskeleton (LINC) complex, the latter spanning through the nuclear envelope and thus bridging ECM-generated signals to the nucleus. LINC rearrangement deforms the nucleus, hence making cryptic DNA domains accessible to stage-specific transcription factors, whose activity is instructed by shuttling mechanosensitive cofactors.