The Impact of the Physical Micro‐Environment on Notch Signaling

Abstract

Notch is a transmembrane ligand receptor that is involved in cell‐cell communication via canonical binding to a mounted ligand on an adjacent cell. Upon activation of ligand binding, Notch's intracellular portion is cleaved and translocates to the nucleus to function as a transcriptional regulator of many downstream genes. Extracellular micro‐environmental cues including shear stress, ECM stiffness, pH, etc. have been shown to impact Notch activation. Integrins are dimerizing proteins that aid in attachment of the cell to the extracellular matrix, which can have impacts on cell physiology from the micro‐environment. Recently published data has also revealed that integrins have an effect on Notch activation, but the mechanism(s) inducing this response have yet to be discovered. Because the extracellular micro‐environments can impact cell physiology through integrin functions, we hypothesize that these physical micro‐environmental conditions may also impact Notch signaling. To investigate this hypothesis, we monitored Notch activation during shear stress or increasing extracellular matrix stiffness, two conditions shown to influence integrin downstream signaling. Our preliminary results show that applying shear stress on endothelial cells provides an increase in downstream Notch signaling activity, which is effected by inhibiting integrin‐linked molecules. Our preliminary results also suggest that Notch activity is controlled by matrix stiffness and that inhibiting Notch activation on stiff extracellular matrix impacts the production of smooth muscle actin (indicator of fibrosis), suggesting a pathway to fibrosis through an integrin‐Notch connection. Together, these experiments support our hypothesis of the impact of the physical microenvironment on Notch signaling through integrin activation. By coming to these conclusions, we hope to gain a better understanding of the impacts integrins and the microenvironment have on Notch signaling and to identify the mechanisms involved.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.