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Review Article

The “Stressful” Life of Cell Adhesion Molecules: On the Mechanosensitivity of Integrin Adhesome

[+] Author and Article Information
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

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

1Corresponding author.

Manuscript received June 30, 2017; final manuscript received December 12, 2017; published online January 18, 2018. Editor: Victor H. Barocas.

J Biomech Eng 140(2), 020807 (Jan 18, 2018) (7 pages) Paper No: BIO-17-1287; doi: 10.1115/1.4038812 History: Received June 30, 2017; Revised December 12, 2017

Cells have evolved into complex sensory machines that communicate with their microenvironment via mechanochemical signaling. Extracellular mechanical cues trigger complex 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 cytoskeleton, 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 determines the type of newly recruited proteins, which in turn modify the local stress distribution. 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 mechanosensitivity in adhesion proteins is discussed herein along with important questions yet to be addressed, are discussed.

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Figures

Grahic Jump Location
Fig. 1

Mechanosensitivity of FA proteins regulates the FA architecture. As mechanical stress impinges on a protein, the molecule 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 complex. Otherwise, the new conformation of protein regulates the strength of its existing interactions, e.g., catch bond formation.

Grahic Jump Location
Fig. 2

The architecture of FAs. FAs can be divided into three functional layers each having a distinct molecular composition. Integrin receptors reside in the lipid membrane and are activated via binding to the talin head within the integrin signaling layer. Other important signaling molecules such as FAK and paxillin also function in the integrin signaling layer. The force transduction layer is rich in vinculin and the rod domain of talin, which is oriented toward actin. Actin and α-actinin are localized within the actin regulatory layer. The distal end of FA connects with the lamellipodial dendritic actin.

Grahic Jump Location
Fig. 3

The retrograde flow of actin. Actin polymerizes at the cell edge, while actomyosin forces are applied to the rear end of actin fibers. The combination of these effects results in a rearward flow of actin relative to the cell edge. The actin retrograde flow is transmitted to the ECM in the form of traction forces via FAs, which act as a “molecular clutch.”

Grahic Jump Location
Fig. 4

The force and lifetime of FA and its components. The lifetime of proteins within the FA structure is in the order of seconds, while FA as a subcellular organism remains stable for several tens of minutes. Early adhesions only consist of a few proteins and last for tens of seconds. As they grow into focal complexes, their lifetime increases to a few minutes. The force that can trigger a mechanical response in a single protein is in the order of 1 to 10 pN, whereas forced exerted by FAs on the substrate is 2–3 orders of magnitude higher. The shade in shapes represents the area of the system, e.g., the FA area increases by force. The area of a single protein is roughly estimated to be in the order of 1 nm2. The bar on the left side of the plot shows the shade scale used for the area in μm2. The left shape representing the “protein” is illustrated as a droplet merging into the “focal adhesion” shown as a larger drop on the right.

Grahic Jump Location
Fig. 5

Modularity of molecular mechanosensitivity. There are similar mechanisms of vinculin recruitment to cell-cell and FA contacts. (a) The VBS of α-catenin is inhibited inside the MI domain. (b) The cytoskeletal forces along α-catenin stretches the molecule and unravels the inhibited VBS. (c) Talin has 11 VBSs along its rod domain, which are inhibited in the absence of mechanical stress. It should be noted that only three VBSs are shown for simplicity. (d) Tension along talin's rod domain increases its affinity for vinculin binding.

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