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Defining Single Molecular Forces Required to Activate Integrin and Notch Signaling

Science  24 May 2013:
Vol. 340, Issue 6135, pp. 991-994
DOI: 10.1126/science.1231041

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Sensing Tension

Many cellular processes are regulated by mechanical signals. Single-molecule force spectroscopy has been used to probe molecular unfolding or unbinding; however, measuring the single-molecule forces required to activate signaling remains a challenge. Wang and Ha (p. 991) describe a “Tension Gauge Tether” approach to measure the force applied on a single receptor ligand bond. By using tethers with a range of tension tolerances and monitoring activation, the force required to activate signaling could be measured.

Abstract

Cell-cell and cell-matrix mechanical interactions through membrane receptors direct a wide range of cellular functions and orchestrate the development of multicellular organisms. To define the single molecular forces required to activate signaling through a ligand-receptor bond, we developed the tension gauge tether (TGT) approach in which the ligand is immobilized to a surface through a rupturable tether before receptor engagement. TGT serves as an autonomous gauge to restrict the receptor-ligand tension. Using a range of tethers with tunable tension tolerances, we show that cells apply a universal peak tension of about 40 piconewtons (pN) to single integrin-ligand bonds during initial adhesion. We find that less than 12 pN is required to activate Notch receptors. TGT can also provide a defined molecular mechanical cue to regulate cellular functions.

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