Cells are capable of relaying mechanical stimuli from their physical environment all the way down to the nucleus through electrochemical, biochemical or mechanical pathways. In many cases the activation or suppression of a given pathway by a mechanical cue gives rise to alterations in gene expression. Mechanical signals initiate biochemical pathways through conformational changes in mechanosenstitive proteins that leads to chemical signal propagation and amplification. These proteins then interact with downstream mediators before eventually reaching the nucleus and initiating changes in gene expression. This final ‘end point’ in the pathway can be achieved through activation of transcription factors, the formation of transcription complexes or through a physical remodeling of chromatin or other nuclear components. Of particular importance in biochemical mechanotransduction are phosphorylation events or other post-translational modifications of proteins, as these events are often associated with changes in transcription. Furthermore, mechanosensitive proteins may also mediate the nuclear translocation of transcriptional regulators, where they bind to specific regulatory sites on DNA to initiate gene expression.
NFκB (nuclear factor kappa light chain enhancer of activated B cells) is a family of highly conserved transcription factors that regulate many important cellular behaviours, in particular, inflammatory responses, cellular growth and apoptosis. NFκB is also involved in diseases such as cancer, arthritis and asthma. NFκB is formed through the homo- or hetero-dimerization of members of the Rel family of DNA binding proteins. In mammals these include RelA (p65), c-rel, RelB, p105 (the precursor of p50), and p100 (the precursor of p52). Each member of this family contains a Rel homology domain (RHD), which itself consists of a DNA binding region, a dimerization region and a nuclear localization signal. NF-κB activity is regulated by family of proteins known as IκBs which include IκBα, IκBβ, IκBγ, IκBε and Bcl-3. When in their inactivated state, NFκB complexes are localized in the cytoplasm, in complex with IκB kinase-α (IKKα), IκB kinase-β (IKKβ) and IKKγ/NEMO, a non-enzymatic protein that may function as a scaffold. The IKK complex can be activated by various cytokines, inflammatory molecules and stress signals. Depending on the composition of NFκB in the nucleus, different genes will be actively transcribed. This variation and specificity in gene targets is further determined by the post translational modification of different subunits, such as the phosphorylation of p65. NFκB has also been identified as a mediator of mechanotransduction in several cell types. This role is carried out through changes in both its activation, and localization, in response to mechanical signals.
Actin filament depolymerization helps to maintain a pool of actin monomers that permits the continual restructuring and growth of the actin cytoskeleton. Disassembly of actin filaments occurs at the pointed end of the filament and is driven by the ADF/cofilin (AC) family of proteins. Actin monomers intrinsically dissociate from the barbed end at a faster rate than they do from the pointed end. This is counteracted by the binding of capping proteins or formins to the barbed end, creating a more stable filament. The action of cofilin at the pointed end serves to destabilize the filament and promote the release of ADP-actin monomers. The destabilized form of actin filaments, which has been compared to that observed in younger filaments, is more prone to filament severing. The higher affinity of ACs for ADP-F-actin relative to ATP-F-actin causes severing in the central regions of filaments where ADP-actin is enriched, though depolymerization at the pointed end also occurs. The phosphorylation of cofilin greatly reduces its F-actin binding and depolymerizing activity. Cofilin phosphorylation in vertebrates is controlled by the activity of Rho GTPase and Lim kinase pathways.