Cell Shape can Dynamically Process Information during Signal Flow in Regulatory Pathways

Abstract

Shape is often an indicator of cell health; however the role of cell shape in signaling is not well understood. There are many factors that influence the interaction between cell shape and signaling including the cytoskeleton, protein scaffolding and crowding. Here,we determined if cell shape alone could process information during signal transduction at the plasma membrane. Using analytical approaches and numerical simulations we studied elliptical shapes since neoplastic transformation often results in cells that are spindle shaped. Mathematical analyses showed that with increasing eccentricity of the cell, receptors diffusing evenly in the plane of the membrane accumulate transiently at regions of high curvature upon binding ligand. This inhomogeneous distribution of activated receptors is periodic and follows the Mathieu function. This transient inhomogeneity arises from local balance between reaction and diffusion of the soluble ligand and membrane-bound diffusion of the receptor. Numerical simulations for the receptor pathways show that these transient microdomains of activated receptors in the membrane amplify signals to downstream protein kinases. For the growth factor receptor pathway, change in cell shape from circle to ellipse results in a nearly two-fold increase in activated MAP-kinase in the nucleus.The model predictions were tested experimentally using patterned cells. Experimental measurements of receptor density and diffusivity show that the EGF receptor activation and diffusion is dependent on the local curvature. Additionally, elliptical cells show a transient spatial inhomogeneity in the activation of signaling components when compared to circular cells in vitro.Thus, cell shape and growth factor signaling can form a multi-scale positive feedback loop that could contribute to the maintenance of the transformed state.