Mechanoregulation of Wound Healing and Skin Homeostasis

Figure 1

Mechanotransduction in transcriptional regulation. Description. Interacting with G-actin inactivates MAL. F-actin polymerization uses up amounts of unpolymerized F-actin and removes the inhibition of MAL through G-actin and released MAL binds to the SRF. This activated SRF binds to DNA and induces transcription. YAP can be inhibited by mechanisms not connected with kinases such as AMOT. AMOT protein binds actin filaments and allows YAP to enter the nucleus. If it comes to F-actin depolymerization, AMOT dissociates from actin and retains YAP in the cytoplasm. When YAP is phosphorylated by LATS, AMOT recruits ubiquitin ligase to AMOT/YAP complex and initiates the YAP proteasome degradation. The protein bound to tight junction ZO-2, together with YAP, enters the nucleus where it inhibits the activity of YAP. The p130 isoform of AMOT acts in the opposite manner and promotes nuclear localization of YAP and acts as a transcriptional cofactor of the YAP-TEAD complex. Rho GTPases control YAP/TAZ activity through canonical GPCR-linked (G-protein coupled receptors) manner or noncanonical activation of YAP through focal adhesion signaling and FAK kinase. It is hypothesized that the presence of F-actin and stress fiber formation (stress fibers) is crucial for the activation of YAP and TAZ. Upon translocation to the nucleus, they associate with TEAD transcription factor which drives transcription of proliferative genes. Rho GTPases and actin associated proteins (CAP-Z Cofilin, Gelsolin) can have a stabilizing effect on the network of actin filaments and directly or indirectly regulate YAP/TAZ translocation to the nucleus. Mechanical forces generated by ECM can be directly transmitted by the cytoskeleton to the nucleus through LINC complex. Mechanical signal transduction is received by nucleoskeleton proteins (laminae, emerin) that directly or indirectly may affect gene expression. Activation of β-catenin and translocation to the nucleus in response to compressive forces. β-catenin is structural component of adherens junctions in epithelial cells, regulating cell-cell interactions. Shuttling of β-catenin between the cytoplasm and nucleus is a key step in this signaling pathway. Unphosphorylated β-catenin can enter the nucleus and activate transcription, despite activation canonical Wnt pathway (adapted from Low et al. [74]).