Department of Mechanical Engineering Fall Seminar Series
“Single-molecule measurements of force transmission by integrin heterodimers in living cells”
Presented by Professor Alexander Dunn, Chemical Engineering, Stanford University
Integrins are heterodimeric transmembrane adhesion proteins that link the cytoskeleton to the extracellular matrix (ECM), and hence play a central role in the construction of complex, multicellular tissues. Although integrins are required for both cellular traction generation and for sensing mechanical cues such as substrate rigidity, the magnitude of the forces born by integrin heterodimers was unclear. We used FRET-based molecular tension sensors to determine the magnitude and origins of the forces experienced by individual integrins in living cells. We found that this distribution was highly skewed, with the majority of integrins bearing loads of ~2 pN, while a tiny subpopulation experienced forces >11 pN. Further experiments revealed that this distribution was controlled in a modular manner: integrin heterodimer usage controlled the number and stability of cellular connections to the ECM, while the proteins that link integrins to the cytoskeleton regulated the distribution of loads borne by individual integrin complexes. These and other observations support a general model for how cells create the regulated and dynamic adhesion complexes that are a defining feature of multicellular life.
Alex Dunn is an Associate Professor in the Department of Chemical Engineering at Stanford University. His research focuses on understanding how living cells sense mechanical stimuli, with particular interests in stem cell biology and tissue engineering. Dr. Dunn worked as a postdoctoral scholar with James Spudich in the Department of Biochemistry at the Stanford University School of Medicine. He received his Ph.D. at the California Institute of Technology under the direction of Harry Gray, where his work focused on understanding the catalytic mechanism selective C-H bond oxidation by cytochrome P450 enzymes. His work has been recognized with numerous awards, including the Hertz Fellowship, Jane Coffin Childs Postdoctoral Fellowship, the Burroughs Wellcome Career Award at the Scientific Interface, and NIH Director’s New Innovator Award.