Figure 1.

Schematic representation of critical protein–protein interactions at cell–extracellular matrix (ECM) adhesion sites in cancer cells grown in low (left) and high (right) stiffness conditions. Several important protein complexes are formed at the cell–ECM sites that are vital for normal cell function. More specifically, integrin-linked kinase (ILK) binds to the cytoplasmic domain of integrins and also interacts with particularly interesting new cysteine–histidine rich protein (PINCH)-1 and parvin alpha (PARVA) forming a stable ternary complex at cell–ECM adhesions known as PIP (PINCH–ILK–PARVA) or IPP (ILK–PINCH–PARVA) complex (31). PARVA, in turn, binds directly to actin connecting the complex to the cytoskeleton of the cell. ILK has also been shown to interact with Kindlin-2 (also known as mitogen-inducible gene-2 or Mig-2) which again forms a protein complex with Migfilin and filamin A (FLNA) (32), an actin-crosslinking protein. Interestingly, Migfilin has been shown to interact with vasodilator-stimulated phosphoprotein (VASP) (14), regulating cell migration. Equally important is the interaction of integrins with talin (33) and paxillin, which in turn binds to focal adhesion kinase (FAK) (34) while FAK binds to Src (35), which has been also shown to interact with Migfilin regulating cell–ECM mediated survival (36). Note that all cell–ECM adhesion proteins have direct or indirect connection to the actin cytoskeleton, while they activate downstream effectors such as the RhoGTPases, and matrix metalloproteinases (MMPs) eventually leading to regulation of vital cellular functions (proliferation, survival, migration, and invasion). Notably, higher stiffness conditions are associated with marked increase in the amount of stress fibers as well as increased migration and invasion.