Hengameh Shams Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, CA 94720-1762 Brenton D. Hoffman Department of Biomedical Engineering, Duke University, Durham, NC 27708 Mohammad R. K. Mofrad 1 Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, 208A Stanley Hall #1762, Berkeley, CA 94720-1762; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Lab, Berkeley, CA 94720 e-mail: mofrad@berkeley.edu The “Stressful” Life of Cell Adhesion Molecules: On the Mechanosensitivity of Integrin Adhesome Cells have evolved into complex sensory machines that communicate with their microen- vironment via mechanochemical signaling. Extracellular mechanical cues trigger com- plex biochemical pathways in the cell, which regulate various cellular processes. Integrin-mediated focal adhesions (FAs) are large multiprotein complexes, also known as the integrin adhesome, that link the extracellular matrix (ECM) to the actin cytoskele- ton, and are part of powerful intracellular machinery orchestrating mechanotransduction pathways. As forces are transmitted across FAs, individual proteins undergo structural and functional changes that involve a conversion of chemical to mechanical energy. The local composition of early adhesions likely defines the regional stress levels and deter- mines the type of newly recruited proteins, which in turn modify the local stress distribu- tion. Various approaches have been used for detecting and exploring molecular mechanisms through which FAs are spatiotemporally regulated, however, many aspects are yet to be understood. Current knowledge on the molecular mechanisms of mechano- sensitivity in adhesion proteins is discussed herein along with important questions yet to be addressed, are discussed. [DOI: 10.1115/1.4038812] Keywords: focal adhesions, mechanosensitivity, force transmission, signaling, proteins The Mystery of Mechanosensitivity: How Mechanical Stimuli Affect Biological Processes? Recently, significant evidence has emerged demonstrating that external mechanical forces, such as fluid shear stress in the vascu- lature or contractile force of cells’ own actomyosin cytoskeleton, are critical determinants of the form and function of cells, tissues, and organisms [1,2]. This process is generally referred to as mechanotransduction and is due to the mechanosensitive func- tional and/or structural changes at the cellular, subcellular, and molecular levels [1,3,4]. Traditionally, biological regulation has been understood from the principles mediating solution biochem- istry, including diffusivities, binding affinities, and reaction rates. Thus, most early work on mechanosensitivity focused on deter- mining how mechanical stimuli could affect these processes [5,6]. An organizing principle has emerged that combines fundamental principles in biochemistry, that protein structure dictates protein function, and biophysics, that protein structure is largely dictated by multitude of rather weak interactions that are readily rear- ranged. Thus, the primary origin of mechanosensitivity is that applied forces induce conformational changes in protein structure as shown by generic protein 1 in Fig. 1 [2]. Similarly, force- induced conformation switching of focal adhesion (FA) proteins is required for regulating new binding events as illustrated by the interaction between mechanically activated proteins 1 and 2 in Fig. 1. For instance, the mechanically regulated association of proteins has been observed for several key structural proteins, including vinculin and talin, vinculin and a-catenin, as well as filamin and FilGAP [7–9]. Also, force can significantly affect sig- naling cascades, as force-induced conformation changes is required for a phosphorylation of p130CAS by Src-family kinases as well as the localization of MAP kinase 1 [10,11]. If the applied force on mechanosensitive proteins does not cause any alterations in the molecular composition, it may cause reinforcement or weakening of existing interactions. Important examples are the catch-bond-behavior of pairwise interactions between integrin, and ligands [12], as well as the interaction of actin with myosin Fig. 1 Mechanosensitivity of FA proteins regulates the FA architecture. As mechanical stress impinges on a protein, the mol- ecule responds by undergoing a conformational change. This may result in formation of new interactions or disruption of existing interactions, which modifies the local composition of the FA com- plex. Otherwise, the new conformation of protein regulates the strength of its existing interactions, e.g., catch bond formation. 1 Corresponding author. Manuscript received June 30, 2017; final manuscript received December 12, 2017; published online January 18, 2018. Editor: Victor H. Barocas. Journal of Biomechanical Engineering FEBRUARY 2018, Vol. 140 / 020807-1 Copyright V C 2018 by ASME Downloaded From: https://biomechanical.asmedigitalcollection.asme.org on 11/30/2018 Terms of Use: http://www.asme.org/about-asme/terms-of-use