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Register a new userDependence of MAPK mediated signaling on Erk isoforms and differences in nuclear shuttling
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The mitogen activated protein kinase (MAPK) family of proteins is involved in regulating cellular fate activities such as proliferation, differentiation and apoptosis. Their fundamental importance has attracted considerable attention on different aspects of the MAPK signaling dynamics; this is particularly true for the Erk/Mek system, which has become the canonical example for MAPK signaling systems. Erk exists in many different isoforms, of which the most widely studied are Erk1 and Erk2. Until recently, these two kinases were considered equivalent as they differ only subtly at the sequence level; however, these isoforms exhibit radically different trafficking between cytoplasm and nucleus. Here we use spatially resolved data on Erk1/2 to develop and analyze spatio-temporal models of these cascades; and we discuss how sensitivity analysis can be used to discriminate between mechanisms. We are especially interested in understanding why two such similar proteins should co-exist in the same organism, as their functional roles appear to be different. Our models elucidate some of the factors governing the interplay between processes and the Erk1/2 localization in different cellular compartments, including competition between isoforms. This methodology is applicable to a wide range of systems, such as activation cascades, where translocation of species occurs via signal pathways. Furthermore, our work may motivate additional emphasis for considering potentially different roles for isoforms that differ subtly at the sequence level.
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Phagocytosis and receptor-mediated endocytosis are vitally important particle uptake mechanisms in many cell types, ranging from single-cell organisms to immune cells. In both processes, engulfment by the cell depends critically on both particle shape and orientation. However, most previous theoretical work has focused only on spherical particles and hence disregards the wide-ranging particle shapes occurring in nature, such as those of bacteria. Here, by implementing a simple model in one and two dimensions, we compare and contrast receptor-mediated endocytosis and phagocytosis for a range of biologically relevant shapes, including spheres, ellipsoids, capped cylinders, and hourglasses. We find a whole range of different engulfment behaviors with some ellipsoids engulfing faster than spheres, and that phagocytosis is able to engulf a greater range of target shapes than other types of endocytosis. Further, the 2D model can explain why some nonspherical particles engulf fastest (not at all) when presented to the membrane tip-first (lying flat). Our work reveals how some bacteria may avoid being internalized simply because of their shape, and suggests shapes for optimal drug delivery.
The mechanisms underlying collective migration, or the coordinated movement of a population of cells, are not well understood despite its ubiquitous nature. As a means to investigate collective migration, we consider a wound healing scenario in which a population of cells fills in the empty space left from a scratch wound. Here we present a simplified mathematical model that uses reaction-diffusion equations to model collective migration during wound healing with an emphasis on cell movement and its response to both cell signaling and cell-cell adhesion. We use the model to investigate the effect of the MAPK signaling cascade on cell-cell adhesion during wound healing after EGF treatment. Our results suggest that activation of the MAPK signaling cascade stimulates collective migration through increases in the pulling strength of leader cells. We further use the model to suggest that treating a cell population with EGF converts the time to wound closure (as function of wound area) from parabolic to linear.
Angiogenesis involves the formation of new blood vessels by sprouting or splitting of existing blood vessels. During sprouting, a highly motile type of endothelial cell, called the tip cell, migrates from the blood vessels followed by stalk cells, an endothelial cell type that forms the body of the sprout. To get more insight into how tip cells contribute to angiogenesis, we extended an existing computational model of vascular network formation based on the cellular Potts model with tip and stalk differentiation, without making a priori assumptions about the differences between tip cells and stalk cells. To predict potential differences, we looked for parameter values that make tip cells (a) move to the sprout tip, and (b) change the morphology of the angiogenic networks. The screening predicted that if tip cells respond less effectively to an endothelial chemoattractant than stalk cells, they move to the tips of the sprouts, which impacts the morphology of the networks. A comparison of this model prediction with genes expressed differentially in tip and stalk cells revealed that the endothelial chemoattractant Apelin and its receptor APJ may match the model prediction. To test the model prediction we inhibited Apelin signaling in our model and in an emph{in vitro} model of angiogenic sprouting, and found that in both cases inhibition of Apelin or of its receptor APJ reduces sprouting. Based on the prediction of the computational model, we propose that the differential expression of Apelin and APJ yields a self-generated gradient mechanisms that accelerates the extension of the sprout.
Two distinct mechanisms for filtering noise in an input signal are identified in a class of adaptive sensory networks. We find that the high frequency noise is filtered by the output degradation process through time-averaging; while the low frequency noise is damped by adaptation through negative feedback. Both filtering processes themselves introduce intrinsic noises, which are found to be unfiltered and can thus amount to a significant internal noise floor even without signaling. These results are applied to E. coli chemotaxis. We show unambiguously that the molecular mechanism for the Berg-Purcell time-averaging scheme is the dephosphorylation of the response regulator CheY-P, not the receptor adaptation process as previously suggested. The high frequency noise due to the stochastic ligand binding-unbinding events and the random ligand molecule diffusion is averaged by the CheY-P dephosphorylation process to a negligible level in E.coli. We identify a previously unstudied noise source caused by the random motion of the cell in a ligand gradient. We show that this random walk induced signal noise has a divergent low frequency component, which is only rendered finite by the receptor adaptation process. For gradients within the E. coli sensing range, this dominant external noise can be comparable to the significant intrinsic noise in the system. The dependence of the response and its fluctuations on the key time scales of the system are studied systematically. We show that the chemotaxis pathway may have evolved to optimize gradient sensing, strong response, and noise control in different time scales
Multiple myeloma is a plasma cell cancer that leads to a dysregulated bone remodeling process. We present a partial differential equation model describing the dynamics of bone remodeling with the presence of myeloma tumor cells. The model explicitly takes into account the roles of osteoclasts, osteoblasts, precursor cells, stromal cells, osteocytes, and tumor cells. Previous models based on ordinary differential equations make the simplifying assumption that the bone and tumor cells are adjacent to each other. However, in actuality, these cell populations are separated by the bone marrow. Our model takes this separation into account by including the diffusion of chemical factors across the marrow, which can be viewed as communication between the tumor and bone. Additionally, this model incorporates the growth of the tumor and the diminishing bone mass by utilizing a ``moving boundary. We present numerical simulations that qualitatively validate our models description of the cell population dynamics.
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