@article{welf_haugh_2012, title={Stochastic dynamics of membrane protrusion mediated by the DOCK180/Rac pathway in migrating cells (vol 3, pg 30, 2010)}, volume={5}, number={4}, journal={Cellular and Molecular Bioengineering}, author={Welf, E. S. and Haugh, J. M.}, year={2012}, pages={514–516} }
 @article{melvin_welf_wang_irvine_haugh_2011, title={In Chemotaxing Fibroblasts, Both High-Fidelity and Weakly Biased Cell Movements Track the Localization of PI3K Signaling}, volume={100}, ISSN={["0006-3495"]}, DOI={10.1016/j.bpj.2011.02.047}, abstractNote={Cell movement biased by a chemical gradient, or chemotaxis, coordinates the recruitment of cells and collective migration of cell populations. During wound healing, chemotaxis of fibroblasts is stimulated by platelet-derived growth factor (PDGF) and certain other chemoattractants. Whereas the immediate PDGF gradient sensing response has been characterized previously at the level of phosphoinositide 3-kinase (PI3K) signaling, the sensitivity of the response at the level of cell migration bias has not yet been studied quantitatively. In this work, we used live-cell total internal reflection fluorescence microscopy to monitor PI3K signaling dynamics and cell movements for extended periods. We show that persistent and properly aligned (i.e., high-fidelity) fibroblast migration does indeed correlate with polarized PI3K signaling; accordingly, this behavior is seen only under conditions of high gradient steepness (>10% across a typical cell length of 50 μm) and a certain range of PDGF concentrations. Under suboptimal conditions, cells execute a random or biased random walk, but nonetheless move in a predictable fashion according to the changing pattern of PI3K signaling. Inhibition of PI3K during chemotaxis is accompanied by loss of both cell-substratum contact and morphological polarity, but after a recovery period, PI3K-inhibited fibroblasts often regain the ability to orient toward the PDGF gradient.}, number={8}, journal={BIOPHYSICAL JOURNAL}, publisher={Elsevier BV}, author={Melvin, Adam T. and Welf, Erik S. and Wang, Yana and Irvine, Darrell J. and Haugh, Jason M.}, year={2011}, month={Apr}, pages={1893–1901} }
 @article{weiger_ahmed_welf_haugh_2010, title={Directional Persistence of Cell Migration Coincides with Stability of Asymmetric Intracellular Signaling}, volume={98}, ISSN={["1542-0086"]}, DOI={10.1016/j.bpj.2009.09.051}, abstractNote={It has long been appreciated that spatiotemporal dynamics of cell migration are under the control of intracellular signaling pathways, which are mediated by adhesion receptors and other transducers of extracellular cues. Further, there is ample evidence that aspects of cell migration are stochastic: how else could it exhibit directional persistence over timescales much longer than typical signal transduction processes, punctuated by abrupt changes in direction? Yet the mechanisms by which signaling processes affect those behaviors remain unclear. We have developed analytical methods for relating parallel live-cell microscopy measurements of cell migration dynamics to the intracellular signaling processes that govern them. In this analysis of phosphoinositide 3-kinase signaling in randomly migrating fibroblasts, we observe that hot spots of intense signaling coincide with localized cell protrusion and endure with characteristic lifetimes that correspond to those of cell migration persistence. We further show that distant hot spots are dynamically and stochastically coupled. These results are indicative of a mechanism by which changes in a cell's direction of migration are determined by a fragile balance of relatively rapid intracellular signaling processes.}, number={1}, journal={BIOPHYSICAL JOURNAL}, publisher={Elsevier BV}, author={Weiger, Michael C. and Ahmed, Shoeb and Welf, Erik S. and Haugh, Jason M.}, year={2010}, month={Jan}, pages={67–75} }
 @article{welf_haugh_2010, title={Stochastic Dynamics of Membrane Protrusion Mediated by the DOCK180/Rac Pathway in Migrating Cells}, volume={3}, ISSN={["1865-5033"]}, DOI={10.1007/s12195-010-0100-8}, abstractNote={Cell migration is regulated by processes that control adhesion to extracellular matrix (ECM) and force generation. While our fundamental understanding of how these control mechanisms are actuated at the molecular level (signal transduction) has been refined over many years, appreciation of their dynamics has grown more recently. Here, we formulate and analyze by stochastic simulation a quantitative model of signaling mediated by the integrin family of adhesion receptors. Nascent adhesions foster the activation of the small GTPase Rac by at least two distinct signaling pathways, one of which involves tyrosine phosphorylation of the scaffold protein paxillin and formation of multiprotein complexes containing the guanine nucleotide exchange factor DOCK180. Active Rac promotes protrusion of the cell’s leading edge, which in turn enhances the rate of nascent adhesion nucleation; we call this feedback mechanism the core protrusion cycle. Protrusion is antagonized by stable adhesions, which form by myosin-dependent maturation of nascent adhesions, and we propose here a feedforward mechanism mediated by the tyrosine kinase c-Src by which this antagonism is regulated so as to allow transient protrusion at higher densities of ECM. We show that this “buffering of inhibition” mechanism, coupled with the core protrusion cycle, is capable of tuning the frequencies of protrusion and adhesion maturation events.}, number={1}, journal={CELLULAR AND MOLECULAR BIOENGINEERING}, publisher={Springer Nature}, author={Welf, Erik S. and Haugh, Jason M.}, year={2010}, month={Mar}, pages={30–39} }
 @article{cirit_krajcovic_choi_welf_horwitz_haugh_2010, title={Stochastic Model of Integrin-Mediated Signaling and Adhesion Dynamics at the Leading Edges of Migrating Cells}, volume={6}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1000688}, abstractNote={Productive cell migration requires the spatiotemporal coordination of cell adhesion, membrane protrusion, and actomyosin-mediated contraction. Integrins, engaged by the extracellular matrix (ECM), nucleate the formation of adhesive contacts at the cell's leading edge(s), and maturation of nascent adhesions to form stable focal adhesions constitutes a functional switch between protrusive and contractile activities. To shed additional light on the coupling between integrin-mediated adhesion and membrane protrusion, we have formulated a quantitative model of leading edge dynamics combining mechanistic and phenomenological elements and studied its features through classical bifurcation analysis and stochastic simulation. The model describes in mathematical terms the feedback loops driving, on the one hand, Rac-mediated membrane protrusion and rapid turnover of nascent adhesions, and on the other, myosin-dependent maturation of adhesions that inhibit protrusion at high ECM density. Our results show that the qualitative behavior of the model is most sensitive to parameters characterizing the influence of stable adhesions and myosin. The major predictions of the model, which we subsequently confirmed, are that persistent leading edge protrusion is optimal at an intermediate ECM density, whereas depletion of myosin IIA relieves the repression of protrusion at higher ECM density.}, number={2}, journal={PLOS COMPUTATIONAL BIOLOGY}, publisher={Public Library of Science (PLoS)}, author={Cirit, Murat and Krajcovic, Matej and Choi, Colin K. and Welf, Erik S. and Horwitz, Alan F. and Haugh, Jason M.}, editor={Asthagiri, Anand R.Editor}, year={2010}, month={Feb} }