Figure 3.

Transforming growth factor β (TGF-β) signaling is intimately linked with the mechanobiology of cells. Dynamic reciprocity is the concept of bidirectional influence of cells and their microenvironment, including adhesions to the extracellular matrix (ECM) and to surrounding cells. Physical linkages between the extracellular microenvironment are created by plasma membrane adhesion receptors, the cytoskeleton, nuclear membrane KASH (Klarsicht, ANC-1, Syne Homology)- and SUN (Sad1p, UNC-84)-domain proteins, and chromatin. KASH- and SUN-domain proteins bind to each other to form linker of nucleoskeleton and cytoskeleton (LINC) complexes that connect the cytoskeleton to the nucleoskeleton. TGF-β signaling plays an important role in this dynamic reciprocity at both the ECM and nuclear levels. Inactive TGF-β binds to latency-associated peptide (LAP) or latent TGF-β binding proteins (LTBPs) in the ECM. ECM degradation or remodeling relieves mechanical tension on the cell down to the nuclear level while simultaneously increasing the bioavailability of active TGF-β. DNA damage can also decrease the structural integrity of this mechanical tension. TGF-β signaling restores this mechanical homeostasis through upregulation of ECM components and DNA repair enzymes. Tumor cells with elevated TGF-β signaling are able to restore mechanical homeostasis despite ongoing ECM remodeling and DNA damage.