Nucleus mechanosensation. Left and right sides indicate relaxed (soft) and mechanically stressed nuclei, respectively. (A and a) High nuclear tension can induce conformational changes in lamin coiled-coil dimers, which sterically inhibits access by kinases (Swift et al., 2013; Buxboim et al., 2014). In a relaxed nucleus, lamins are more phosphorylated and solubilized into the nucleoplasm (as during cell division). Phospho-solubilized lamins may ultimately become degraded (Bertacchini et al., 2013; Buxboim et al., 2014). Tension-inhibited turnover of lamins is similar to that of collagen I (Flynn et al., 2010) and is an example of structural proteins exhibiting stress-strengthening properties. (B and b) Pulling on nesprin-1 leads to phosphorylation of emerin by Src kinases (Guilluy et al., 2014) and results in stress stiffening of the nucleus. Emerin phosphorylation is high in cells cultured on stiff substrates and regulates many downstream mechanoresponses, including formation of stress fibers, migration, localization of YAP and TAZ, and SRF transcription. (C and c) Mechanosensitive transcription factors such as YAP and TAZ translocate into the nucleus under stress to modulate gene expression (Dupont et al., 2011). (D and d) Mechanical stress leads to nuclear localization of RARγ, which directly regulates LMNA transcription. Nuclear translocation of RARγ is facilitated by its interactions with SUN2 as well as lamin A/C, suggesting a feedback mechanism wherein the protein product lamin A/C regulates its own transcription (Swift et al., 2013). (E and e) Application of mechanical force may lead to changes in chromatin conformation (e.g., local stretching of genes), thereby altering transcriptional activity (Tajik et al., 2016). Mechanical perturbation can also affect the global arrangement of chromosome territories (Maharana et al., 2016). (F) High tension can induce membrane dilation and may lead to transient ruptures, allowing for the exchange and mislocalization of nucleoplasmic and cytoplasmic factors.