SIMPLE RHO GTPASE DYNAMICS GENERATE A COMPLEX REGULATORY LANDSCAPE ASSOCIATED WITH CELL SHAPE

Abstract Migratory cells exhibit a variety of morphologically distinct responses to their environments that manifest in their cell shape. Some protrude uniformly to increase substrate contacts, others are broadly contractile, some polarize to facilitate migration, and yet others exhibit mixtures of these responses. Prior studies have identified a discrete collection of shapes that the majority of cells display and demonstrated that activity levels of the cytoskeletal regulators Rac1 and RhoA GTPase regulate those shapes. Here we use computational modeling to assess whether known GTPase dynamics can give rise to a sufficient diversity of spatial signaling states to explain the observed shapes. Results show that the combination of auto-activation and mutually-antagonistic cross-talk between GTPases along with the conservative membrane binding generates a wide array of distinct homogeneous and polarized regulatory phenotypes that arise for fixed model parameters. From a theoretical perspective, these results demonstrate that simple GTPase dynamics can generate complex multi-stability, where six distinct stable steady-states (three homogeneous and three polarized) co-exist for a fixed set of parameters, each of which naturally maps to an observed morphology. From a biological perspective, while we do not explicitly model the cytoskeleton or resulting cell morphologies, these results, along with prior literature linking GTPase activity to cell morphology, support the hypothesis that GTPase signaling dynamics can generate the broad morphological characteristics observed in many migratory cell populations. Further, the observed diversity may be the result of cells populating a complex morphological landscape generated by GTPase regulation rather than being the result of intrinsic cell-cell variation. These results demonstrate that Rho GTPases may have a central role in regulating the broad characteristics of cell shape (e.g., expansive, contractile, polarized, etc.) and that shape heterogeneity may be (at least partly) a reflection of the rich signaling dynamics regulating the cytoskeleton rather than intrinsic cell heterogeneity.