Introduction: Mechanical Force Can Regulate Molecular Function

Cells can sense and transduce a broad range of mechanical forces into distinct sets of biochemical signals that ultimately regulate cellular processes, including adhesion, migration, proliferation, differentiation, and apoptosis. But how is force translated at the molecular level into biochemical signal changes that have the potential to alter cellular behavior? Is it just the rigidity of matrices that is sensed by cells, or can force applied to the extracellular matrix switch their functional display? How about other proteins that are part of the force-bearing protein networks that connect the extracellular matrix to the contractile cytoskeleton: Can their molecular recognition sites be altered if mechanically stretched? The advent of nanotech tools, particularly atomic force microscopy and optical tweezers (Fisher et al., 2000; Kellermayer et al., 1997; Rief et al., 1997; Tanase et al., 2007; Tskhovrebova et al., 1997), were a major milestone in recognizing the unique mechanical properties of proteins. After a decade of new insights into single molecule mechanics, the focus now turns to addressing how force-induced mechanical unfolding could potentially change protein functions (for reviews, see Bustamante et al., 2004; Discher et al., 2005; Gao et al., 2006; Giannone and Sheetz, 2006; Orr et al., 2006; Vogel, 2006; Vogel and Sheetz, 2006). Beyond the molecular recognition sites that confer biochemical specificity to proteins, are there common mechanical design criteria by which structural motifs are assembled to confer unique mechanical properties to proteins? If so, is it possible that cell generated tension is sufficient to mechanically unfold proteins that are part of force-bearing protein networks in living tissues? How are proteins stabilized against mechanical unfolding, and do cells switch protein functions by force to regulate or even switch between intracellular signaling networks?