1. Membrane Trafficking: In this project, we investigated the functional role of the BAR and F-BAR domain proteins in yeast endocytosis. Our research showed that cooperation between robust actin polymerization, and F-BAR and BAR domain proteins, and synaptojanin, is important for membrane scission. Spatio-temporal and functional information together with our theoretical modeling suggest the following picture of endocytosis: F-BAR proteins stabilize the endocytic site, while actin assembly and BAR proteins cooperate for invagination and scission. This paper is currently under review in PNAS. 2. Kinetochore motility: Based on the histogram of the neighboring distance between kinetochore ring along microtubule, I contructed a statistical model to differentiate whether the rings can diffuse or not. Our research shows that kinetochore ring must be highly diffusive. The paper is published in Mol. Biol. Cell. 3. Microtubule sequestration effects in mitosis: The commonly recognized mechanisms for spatial regulation inside the cell are membrane-bounded compartmentalization and biochemical association with subcellular organelles. We use computational modeling to investigate another spatial regulation mechanism mediated by the microtubule network in the cell. Our results demonstrate that the mitotic spindle can impose strong sequestration and concentration effects on molecules with binding affinity for microtubules, especially dynein-directed cargoes. The model can recapitulate the essence of three experimental observations on distinct microtubule network morphologies: the sequestration of germ plasm components by the mitotic spindles in the Drosophila syncytial embryo, the asymmetric cell division initiated by the time delay in centrosome maturation in the Drosophila neuroblast, and the diffusional block between neighboring nuclei in the Drosophila syncytial embryo. Our model thus suggests that cell cycle-dependent change in the microtubule network is critical for achieving different spatial regulation effects;that is, the microtubule network provides a spatially extensive docking platform for molecules and gives rise to a structured cytoplasm, in contrast to a free and fluid environment. This paper is currently under review in Current Biology. 4. Asymmetric Furrow ingression during cytokinesis: We construct a minimal model on the contractility of actomyosin ring during cytokinesis. Our model proposes that the local geometry of the furrow site, such as the Gaussian curvature of the membrane, could promote the alignment process of actomyosin filament, which in turn governs the efficiency of the local contractility. As the more the local actomyosin filament contracts, the larger the local Gaussian curvature would become. We show that this mechanism can quantitatively account for all the three modes of actomyosin contractility, depending on the coupling strength of the positive feedback between the local membrane curvature and actomyosin contractility. More importantly, our experimental testing corroborates several predictions unique to our model, suggesting an emergent mechanism of curvature-mediated positive feedback for cytokinetic actomyosin contractility. Furthermore, the model demonstrate that asymmetric furrow ingression is energetically more efficient, thereby suggesting a real functional role of the asymmetry in cytokinetic ring contraction. This model is the first of its kinds. This paper is currently under review in Science. 5. Force-velocity relationship of branching actin network: Actin networks, acting as an engine pushing against an external load, are fundamentally important to cell motility. A measure of the effectiveness of an engine is the velocity the engine is able to produce at a given force, the force-velocity curve. One type of force-velocity curve, consisting of a concave region where velocity is insensitive to increasing force followed by a decrease in velocity, is indicative of an adaptive response. In contrast, an engine whose velocity rapidly decays as a convex curve in response to increasing force would indicate a lack of adaptive response. Interestingly, even taken outside of a cellular context, branching actin networks have been observed to exhibit both concave and convex force-velocity curves. However, the exact mechanism that can explain both force-velocity curves is not yet known. We carried out an agent-based stochastic simulation to explore such a mechanism. Our results suggest that upon loading, branching actin networks are capable of remodeling by increasing the number filaments growing against the load. The remodeling depends not only on the biochemistry of actin filaments but is also dependent upon the time-scale of the network and the load. The model predicts that shortly after encountering resistance ( seconds), the actin network does not have enough time to remodel itself. The force-velocity relationship immediately after application of the load is therefore always convex. A concave force-velocity relationship requires network remodeling at longer time-scales ( minutes). Our model thus provides a mechanism that can account for both convex and concave force-velocity relationships observed in branching actin networks. This paper is currently under review in PNAS. 6. Mechanochemistry of focal adhesion formation: Focal adhesions are essential to mediate cell extracellular matrix (ECM) adhesion and force transmission during cell motilities, which involve the crosstalk between physical signals such as contractile forces or membrane dynamics, and chemical signaling events such as focal adhesion kinase related regulation pathways. However, the underline mechanism of the biophysical regulations of force transmission among actin cytoskeleton, cell membrane, focal complex and ECM remains poorly understood. We collaborated with Dr. Clare Waterman, and constructed a mathematical model to understand the behavior of focal adhesion complex under different experimental conditions. By integrating the cell membrane dynamics, actin network fluid dynamics, and the mechanochemistry of focal complex, the model reveals itself the capability to capture the essential characteristics of focal adhesions in cell motility. In particular, the model explains the heterogeneous traction force and tyrosine kinase activities within focal adhesions at different ECM stiffness. The model thus provides a comprehensive vision of the focal adhesion dynamics. This paper is currently in preparation for publication.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2011
Total Cost
$1,216,245
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Hu, Longhua; Vecchiarelli, Anthony G; Mizuuchi, Kiyoshi et al. (2017) Brownian ratchet mechanisms of ParA-mediated partitioning. Plasmid 92:12-16
Wu, Zhanghan; Plotnikov, Sergey V; Moalim, Abdiwahab Y et al. (2017) Two Distinct Actin Networks Mediate Traction Oscillations to Confer Focal Adhesion Mechanosensing. Biophys J 112:780-794
Stephens, Thomas; Wu, Zhanghan; Liu, Jian (2017) Mechanics of post-fusion exocytotic vesicle. Phys Biol 14:035004
Hu, Longhua; Vecchiarelli, Anthony G; Mizuuchi, Kiyoshi et al. (2017) Brownian Ratchet Mechanism for Faithful Segregation of Low-Copy-Number Plasmids. Biophys J 112:1489-1502
Dorn, Jonas F; Zhang, Li; Phi, Tan-Trao et al. (2016) A theoretical model of cytokinesis implicates feedback between membrane curvature and cytoskeletal organization in asymmetric cytokinetic furrowing. Mol Biol Cell 27:1286-99
Chen, Jing; Liu, Jian (2016) Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint. Biophys J 111:1064-77
Hu, Longhua; Vecchiarelli, Anthony G; Mizuuchi, Kiyoshi et al. (2015) Directed and persistent movement arises from mechanochemistry of the ParA/ParB system. Proc Natl Acad Sci U S A 112:E7055-64
Liu, Jian (2015) The ghost in the machine: is the bacterial chromosome a phantom chain? Biophys J 108:20-1
Chen, Jing; Liu, Jian (2014) Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint. Nat Commun 5:4795
Smith, Daniel B; Liu, Jian (2013) Branching and capping determine the force-velocity relationships of branching actin networks. Phys Biol 10:016004

Showing the most recent 10 out of 12 publications