Cell migration is a fundamental process that plays a crucial role in a wide array of physiological and developmental scenarios, such as immune response, wound healing, stem cell homing and embryogenesis. On the other hand, its dysregulation often results in different detrimental outcomes, including autoimmune diseases, cognitive deficits and cancer metastasis. As an upshot of extensive research for the past three decades, many signal transduction and cytoskeletal molecules have been identified that collectively work to sense and process different external cues, generate proper polarity and help the cell to correctly navigate via coordinated protrusions and contractions. While numerous specific interactions among many such signaling and cytoskeletal molecules have been deduced through biochemical and genetic analyses, how the activities of so many different components are spatially and temporally coordinated at the subcellular scale has remained unclear. In other words, little was known about the global scale organization mechanisms that determine when and where the next protrusions will form or how polarity will be organized in a migrating cell.
My research, carried out in the labs of Peter N. Devreotes
and Pablo A. Iglesias
, answered these fundamental questions on cell migration and signal transduction. We demonstrated that the dynamic regulation of inner membrane surface potential is sufficient and necessary to regulate the cell polarity and migration mode. We developed novel monitoring tools and optogenetic actuators that can work in conjunction with standard live- cell imaging setup and genetic/pharmacological perturbations. Using these systems, we established that surface charge on the inner leaflet of the plasma membrane, a biophysical property — not some coincidental congruence of stepwise specific biomolecular interactions — spatially and temporally orchestrate signal transduction activities in the cell to control protrusion formation. Our experiments in Dictyostelium amoeba
and different mammalian cells demonstrated that surface charge is dynamically altered during signaling network activation and, in turn, its generic perturbation can induce or inhibit signaling activities that mediate cell migration. It is well known that during propagation of nerve impulse, transmembrane potential can regulate the opening of the specific ion channels, which in turn collectively define the transmembrane potential. Our results indicated that transiently lowered inner membrane surface potential, which we termed “action surface potential,” can analogously propagate and interact with signaling network activation.