@article{liu_welf_haugh_2015, title={Linking morphodynamics and directional persistence of T lymphocyte migration}, volume={12}, ISSN={["1742-5662"]}, DOI={10.1098/rsif.2014.1412}, abstractNote={T cells play a central role in the adaptive immune response, and their directed migration is essential for homing to sites of antigen presentation. Like neutrophils, T lymphocytes are rapidly moving cells that exhibit amoeboid movement, characterized by a definitive polarity with F-actin concentrated at the front and myosin II elsewhere. In this study, we used total internal reflection fluorescence (TIRF) microscopy to monitor the cells' areas of contact with a surface presenting adhesive ICAM-1 and the chemokine, CXCL12/SDF-1. Our analysis reveals that T-cell migration and reorientation are achieved by bifurcation and lateral separation of protrusions along the leading membrane edge, followed by cessation of one of the protrusions, which acts as a pivot for cell turning. We show that the distribution of bifurcation frequencies exhibits characteristics of a random, spontaneous process; yet, the waiting time between bifurcation events depends on whether or not the pivot point remains on the same side of the migration axis. Our analysis further suggests that switching of the dominant protrusion between the two sides of the migration axis is associated with persistent migration, whereas the opposite is true of cell turning. To help explain the bifurcation phenomenon and how distinct migration behaviours might arise, a spatio-temporal, stochastic model describing F-actin dynamics is offered.}, number={106}, journal={JOURNAL OF THE ROYAL SOCIETY INTERFACE}, author={Liu, Xiaji and Welf, Erik S. and Haugh, Jason M.}, year={2015}, month={May} } @article{welf_johnson_haugh_2013, title={Bidirectional coupling between integrin-mediated signaling and actomyosin mechanics explains matrix-dependent intermittency of leading-edge motility}, volume={24}, ISSN={["1939-4586"]}, DOI={10.1091/mbc.e13-06-0311}, abstractNote={ Animal cell migration is a complex process characterized by the coupling of adhesion, cytoskeletal, and signaling dynamics. Here we model local protrusion of the cell edge as a function of the load-bearing properties of integrin-based adhesions, actin polymerization fostered by adhesion-mediated signaling, and mechanosensitive activation of RhoA that promotes myosin II–generated stress on the lamellipodial F-actin network. Analysis of stochastic model simulations illustrates how these pleiotropic functions of nascent adhesions may be integrated to govern temporal persistence and frequency of protrusions. The simulations give mechanistic insight into the documented effects of extracellular matrix density and myosin abundance, and they show characteristic, nonnormal distributions of protrusion duration times that are similar to those extracted from live-cell imaging experiments. Analysis of the model further predicts relationships between measurable quantities that reflect the partitioning of stress between tension on F-actin–bound adhesions, which act as a molecular clutch, and dissipation by retrograde F-actin flow. }, number={24}, journal={MOLECULAR BIOLOGY OF THE CELL}, publisher={American Society for Cell Biology (ASCB)}, author={Welf, Erik S. and Johnson, Heath E. and Haugh, Jason M.}, year={2013}, month={Dec}, pages={3945–3955} } @article{welf_ahmed_johnson_melvin_haugh_2012, title={Migrating fibroblasts reorient directionality by a metastable, PI3K-dependent mechanism}, volume={197}, ISSN={["1540-8140"]}, DOI={10.1083/jcb.201108152}, abstractNote={Mesenchymal cell migration as exhibited by fibroblasts is distinct from amoeboid cell migration and is characterized by dynamic competition among multiple protrusions, which determines directional persistence and responses to spatial cues. Localization of phosphoinositide 3-kinase (PI3K) signaling is thought to play a broadly important role in cell motility, yet the context-dependent functions of this pathway have not been adequately elucidated. By mapping the spatiotemporal dynamics of cell protrusion/retraction and PI3K signaling monitored by total internal reflection fluorescence microscopy, we show that randomly migrating fibroblasts reorient polarity through PI3K-dependent branching and pivoting of protrusions. PI3K inhibition did not affect the initiation of newly branched protrusions, nor did it prevent protrusion induced by photoactivation of Rac. Rather, PI3K signaling increased after, not before, the onset of local protrusion and was required for the lateral spreading and stabilization of nascent branches. During chemotaxis, the branch experiencing the higher chemoattractant concentration was favored, and, thus, the cell reoriented so as to align with the external gradient.}, number={1}, journal={JOURNAL OF CELL BIOLOGY}, publisher={Rockefeller University Press}, author={Welf, Erik S. and Ahmed, Shoeb and Johnson, Heath E. and Melvin, Adam T. and Haugh, Jason M.}, year={2012}, month={Apr}, pages={105–114} } @inproceedings{welf_haugh_2012, title={Stochastic models of cell protrusion arising from spatiotemporal signaling and adhesion dynamics}, volume={110}, booktitle={Methods in cell biology, vol 110: computational methods in cell biology}, author={Welf, E. S. and Haugh, J. M.}, year={2012}, pages={223–241} } @article{welf_haugh_2011, title={Signaling pathways that control cell migration: models and analysis}, volume={3}, ISSN={["1939-005X"]}, DOI={10.1002/wsbm.110}, abstractNote={AbstractDissecting the intracellular signaling mechanisms that govern the movement of eukaryotic cells presents a major challenge, not only because of the large number of molecular players involved, but even more so because of the dynamic nature of their regulation by both biochemical and mechanical interactions. Computational modeling and analysis have emerged as useful tools for understanding how the physical properties of cells and their microenvironment are coupled with certain biochemical pathways to actuate and control cell motility. In this focused review, we highlight some of the more recent applications of quantitative modeling and analysis in the field of cell migration. Both in modeling and experiment, it has been prudent to follow a reductionist approach in order to characterize what are arguably the principal modules: spatial polarization of signaling pathways, regulation of the actin cytoskeleton, and dynamics of focal adhesions. While it is important that we ‘cut our teeth’ on these subsystems, focusing on the details of certain aspects while ignoring or coarse‐graining others, it is clear that the challenge ahead will be to characterize the couplings between them in an integrated framework. WIREs Syst Biol Med 2011 3 183–190 DOI: 10.1002/wsbm.110.This article is categorized under: Analytical and Computational Methods > Analytical Methods Models of Systems Properties and Processes > Cellular Models Biological Mechanisms > Cell Signaling }, number={2}, journal={WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE}, publisher={Wiley-Blackwell}, author={Welf, Erik S. and Haugh, Jason M.}, year={2011}, pages={231–240} }