Strain-Activated Signaling within Cell Adhesions Dictates Cell Fate

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Just like steel girders hold up buildings, extracellular matrix fibers help hold tissues together. Cells within tissues act like people in buildings: they adhere to and crawl on extracellular matrix like people walk on the floors. Unlike people however, cells also pull against their matrix and can respond to the stiffness of this adjacent matrix. Normally, stem cells respond simply by maturing into the cells already present in the tissue. However diseases often cause these fibers to become stiffer than normal, which makes the stem cells within these tissues respond inappropriately; cells that typically become muscle instead mature into bone. While we have made such observations, our understanding of why this occurs is limited. Thus a systematic examination of how physical cues like stiffness are converted into biochemical cues that a stem cell can interpret is greatly needed. One of the ways that cells can sense the stiffness of the tissues that surround them is through the unfolding of particular molecules from the forces of cellular contraction. Using computer analysis of known protein structures, the investigator has identified two strong candidates for molecules that will unfold and allow the cells to measure force. Cell chemical pathways identified through this study could be targeted in genetic therapies to treat diseases that stiffen tissues such as cancer and heart disease. Cells sense extracellular matrix properties by contracting against it and converting that information into biochemical readouts in a process called mechanotransduction. Despite understanding the inputs and outputs of this process, little is known about mechanically induced signaling that occurs in between these observations. Stem cells are ideally suited to elucidate these molecular details because they present a "blank slate" where maturation into specific tissues can describe the sensitivity of a physical-to-chemical sensor, i.e. fat cells are less contractile than muscle and bone cells. This research will combine current molecular tools and engineering approaches to test whether proteins within a cell adhesion act as a "molecular strain gauge," i.e. it exposes cryptic kinase binding sites under strain. A bioinformatics-based screen has identified 3 proteins with cryptic kinase binding sites, e.g. SORBS1, SORBS3, and vinculin; project objectives will use in situ fluorescence resonance energy transfer assays to describe cellular strain-induced conformational changes in these proteins and validate the "molecular strain gauge" model for signaling. It will also confirm the function of new mechanosensors, which could be used as therapeutic targets to make stem cells insensitive to tissue stiffening.