scholarly journals Actomyosin Contractility Drives Bile Regurgitation as an Early Homeostatic Response to Increased Biliary Pressure in Obstructive Cholestasis

2016 ◽  
Author(s):  
Kapish Gupta ◽  
Qiushi Li ◽  
Jun Jun Fan ◽  
Eliza Li Shan Fong ◽  
Ziwei Song ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Canalicular Membrane ◽  
Actin Cortex ◽  
Actomyosin Contractility ◽  
Molecular Events ◽  
Pressure Threshold ◽  
Wide Range ◽  
Obstructive Cholestasis ◽  
Biliary Pressure ◽  
Homeostatic Response

AbstractA wide range of liver diseases manifest as biliary obstruction, or cholestasis. However, the sequence of molecular events triggered as part of the early hepatocellular homeostatic response to abnormal elevations in biliary pressure remains poorly elucidated. Bile canaliculi are dynamic luminal structures that undergo actomyosin-mediated periodic contractions to propel secreted bile. Additionally, pericanalicular actin is accumulated during obstructive cholestasis. Therefore, we hypothesize that the pericanalicular actin cortex undergoes significant remodeling as a regulatory response against increased biliary pressure. Here, we report that, actomyosin contractility induces transient deformations along the canalicular membrane, a process we have termed inward blebbing. We show that these membrane intrusions are initiated by local ruptures in the pericanalicular actin cortex, and they typically retract following repair by actin polymerization and actomyosin contraction. However, above a certain osmotic pressure threshold, these inward blebs pinch away from the canalicular membrane into the hepatocyte cytoplasm as large vesicles (2-8 µm). Importantly, we show that these vesicles aid in the regurgitation of bile from the canalicular system. Conclusion: Actomyosin contractility induces the formation of bile-regurgitative vesicles, thus serving as an early homeostatic mechanism against increased biliary pressure during cholestasis.

scholarly journals Myosin-II activity generates a dynamic steady state with continuous actin turnover in a minimal actin cortex

2018 ◽  
Author(s):  
Sonal ◽  
Kristina A. Ganzinger ◽  
Sven K. Vogel ◽  
Jonas Mücksch ◽  
Philipp Blumhardt ◽  
...  
Keyword(s):  
Steady State ◽  
Actin Polymerization ◽  
Myosin Ii ◽  
Fine Tuning ◽  
Cellular Functions ◽  
Actin Cortex ◽  
Actin Turnover ◽  
Cytoskeletal Dynamics

ABSTRACTDynamic reorganization of the actomyosin cytoskeleton allows a fine-tuning of cell shape that is vital to many cellular functions. It is well established that myosin-II motors generate the forces required for remodeling the cell surface by imparting contractility to actin networks. An additional, less understood, role of myosin-II in cytoskeletal dynamics is believed to be in the regulation of actin turnover; it has been proposed that myosin activity increases actin turnover in various cellular contexts, presumably by contributing to disassembly. In vitro reconstitution of actomyosin networks has confirmed the role of myosin in actin network disassembly, but factors such as diffusional constraints and the use of stabilized filaments have thus far limited the observation of myosin-assisted actin turnover in these networks. Here, we present the reconstitution of a minimal dynamic actin cortex where actin polymerization is catalyzed on the membrane in the presence of myosin-II activity. We demonstrate that myosin activity leads to disassembly and redistribution in this simplified cortex. Consequently, a new dynamic steady state emerges in which actin filaments undergo constant turnover. Our findings suggest a multi-faceted role of myosin-II in fast remodeling of the eukaryotic actin cortex.

scholarly journals Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis

2021 ◽  
Author(s):  
Kei Yamamoto ◽  
Haruko Miura ◽  
Motohiko Ishida ◽  
Satoshi Sawai ◽  
Yohei Kondo ◽  
...  
Keyword(s):  
Traction Force ◽  
Tissue Mechanics ◽  
Light Illumination ◽  
Type I ◽  
Contractile Ring ◽  
Cortical Tension ◽  
Regulatory Light Chains ◽  
Actomyosin Contractility ◽  
Nonmuscle Myosin Ii ◽  
Wide Range

Actomyosin contractility generated cooperatively by nonmuscle myosin II and actin filaments plays essential roles in a wide range of biological processes, such as cell motility, cytokinesis, and tissue morphogenesis. However, it is still unknown how actomyosin contractility generates force and maintains cellular morphology. Here, we demonstrate an optogenetic method to induce relaxation of actomyosin contractility. The system, named OptoMYPT, combines a catalytic subunit of the type I phosphatase-binding domain of MYPT1 with an optogenetic dimerizer, so that it allows light-dependent recruitment of endogenous PP1c to the plasma membrane. Blue-light illumination was sufficient to induce dephosphorylation of myosin regulatory light chains and decrease in traction force at the subcellular level. The OptoMYPT system was further employed to understand the mechanics of actomyosin-based cortical tension and contractile ring tension during cytokinesis. We found that the relaxation of cortical tension at both poles by OptoMYPT accelerated the furrow ingression rate, revealing that the cortical tension substantially antagonizes constriction of the cleavage furrow. Based on these results, the OptoMYPT system will provide new opportunities to understand cellular and tissue mechanics.

scholarly journals Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Glycobiology ◽  
2020 ◽  
Author(s):  
Kaitlyn A Dorsett ◽  
Michael P Marciel ◽  
Jihye Hwang ◽  
Katherine E Ankenbauer ◽  
Nikita Bhalerao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Sialic Acids ◽  
Invasion Resistance ◽  
Cell Behaviors ◽  
Molecular Events ◽  
Wide Range

Abstract The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress, and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional, and post-translational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

scholarly journals DDR1 autophosphorylation is a result of aggregation into dense clusters

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
David S. Corcoran ◽  
Victoria Juskaite ◽  
Yuewei Xu ◽  
Frederik Görlitz ◽  
Yuriy Alexandrov ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Super Resolution ◽  
Activation Kinetics ◽  
Molecular Events ◽  
Wide Range ◽  
Human Disorders ◽  
Resolution Imaging ◽  
Collagen Receptor

AbstractThe collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.

The Biochemistry and Molecular Biology of Starch Synthesis in Cereals

1995 ◽  
Vol 22 (4) ◽  
pp. 647 ◽  
Author(s):  
MK Morell ◽  
S Rahman ◽  
SL Abrahams ◽  
R Appels
Keyword(s):  
Molecular Biology ◽  
Starch Synthesis ◽  
Industrial Applications ◽  
Molecular Structures ◽  
End User ◽  
Biochemical Processes ◽  
Starch Quality ◽  
Molecular Events ◽  
Wide Range ◽  
Broad Outline

Starch is a key constituent of plant products finding utility as both a major component of a wide range of staple and processed foods, and as a feedstock for industrial processes. While there has traditionally been a focus on the quantity of starch production, starch quality is of increasing importance to the end-user as consumer demands become more sophisticated and as the range of industrial applications of starch broadens. Determinants of starch quality include the amylose to amylopectin ratio, the distribution of molecular structures within these fractions, and the packaging of the starch in granules. The biochemical processes involved in the transformation of the sucrose delivered to the endosperm cytosol to starch in the amyloplast are understood in broad outline. The importance of particular isoenzymes or processes to the production of starches of specific structures are, however, not well understood. This paper reviews aspects of the physiology, biochemistry and molecular biology of starch in plants, with an emphasis on the synthesis of starch in the cereal endosperm. Progress in understanding the linkages between the molecular events in starch synthesis and developing strategies for the manipulation of starch quantity and quality in cereals are discussed.

scholarly journals The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

2007 ◽  
Vol 18 (10) ◽  
pp. 3860-3872 ◽  
Author(s):  
Justin G. Peacock ◽  
Ann L. Miller ◽  
William D. Bradley ◽  
Olga C. Rodriguez ◽  
Donna J. Webb ◽  
...  
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Actin Polymerization ◽  
Focal Adhesions ◽  
Fiber Formation ◽  
Cell Periphery ◽  
Related Gene ◽  
Cell Contractility ◽  
Fibroblast Migration ◽  
Actomyosin Contractility

In migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin–dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Abl family kinases inhibit cell migration on FN. We provide evidence here that the Abl-related gene (Arg/Abl2) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg−/− fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg−/− fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain–containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg−/− cells, the increased contractility of arg−/− cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.

scholarly journals Modeling the three-way feedback between cellular contractility, actin polymerization, and adhesion turnover resolves the contradictory effects of RhoA and Rac1 on endothelial junction dynamics

2021 ◽  
Author(s):  
Eoin McEvoy ◽  
Tal Sneh ◽  
Emad Moeendarbary ◽  
Gloria E Marino ◽  
Xingyu Chen ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Dynamic Rupture ◽  
Modeling Framework ◽  
Cell Contractility ◽  
Wide Range ◽  
Rho Family ◽  
Rhoa Signaling ◽  
Endothelial Junction

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to atherosclerosis and tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the maintenance of endothelial junctions as dependent on the crosstalk between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Our theoretical model reveals that active cell tension can stabilize cadherin bonds within an adhesion, but excessive RhoA signaling can drive bond dissociation and junction failure. While Rac1-mediated actin polymerization aids gap closure, high levels of Rac1 may also facilitate junction weakening. Combining the modeling framework with novel experiments, we identify how dynamic rupture and heal cycles emerge and, further, describe why gaps tend to localize at multi-cell contacts. Beyond, our analysis also indicates that a critical balance between RhoA and Rac1 expression is required to maintain junction stability and limit endothelial dysfunction. The model predicts how pharmacological modulation of actin polymerization and cell contractility impacts junction stability, with predictions subsequently validated experimentally. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

scholarly journals Pulsatile contractions and pattern formation in excitable active gels

2021 ◽  
Author(s):  
Michael F. Staddon ◽  
Edwin M. Munro ◽  
Shiladitya Banerjee
Keyword(s):  
Regulatory Networks ◽  
Mechanical Forces ◽  
Polymer Gel ◽  
Actin Cortex ◽  
Upstream Regulator ◽  
Cellular Environment ◽  
Chemical Signalling ◽  
Wide Range ◽  
Spatial Propagation ◽  
Quantitative Understanding

The actin cortex is an active adaptive material, embedded with complex regulatory networks that can sense, generate and transmit mechanical forces. The cortex can exhibit a wide range of dynamic behaviours, from generating pulsatory contractions and traveling waves to forming highly organised structures such as ordered fibers, contractile rings and networks that must adapt to the local cellular environment. Despite the progress in characterising the biochemical and mechanical components of the actin cortex, our quantitative understanding of the emergent dynamics of this mechanochemical system is limited. Here we develop a mathematical model for the RhoA signalling network, the upstream regulator for actomyosin assembly and contractility, coupled to an active polymer gel, to investigate how the interplay between chemical signalling and mechanical forces govern the propagation of contractile stresses and patterns in the cortex. We demonstrate that mechanical feedback in the excitable RhoA system, through dilution and concentration of chemicals, acts to destabilise homogeneous states and robustly generate pulsatile contractions. While moderate active stresses generate spatial propagation of contraction pulses, higher active stresses assemble localised contractile structures. Moreover, mechanochemical feedback induces memory in the active gel, enabling long-range propagation of transient local signals.

scholarly journals H+/K+ ion pump enhances cytoskeletal polarity to drive gastrulation in sea urchin embryo

2021 ◽  
Author(s):  
Kaichi Watanabe ◽  
Yuhei Yasui ◽  
Yuta Kurose ◽  
Masashi Fujii ◽  
Takashi Yamamoto ◽  
...  
Keyword(s):  
Sea Urchin ◽  
Actin Polymerization ◽  
Driving Forces ◽  
Ph Control ◽  
Structural Features ◽  
Normal Embryo ◽  
Ion Pump ◽  
Sea Urchin Embryos ◽  
Molecular Events ◽  
Sea Urchin Embryo

Gastrulation is a universal process in the morphogenesis of many animal embryos. In sea urchin embryos, it involves the invagination of single-layered vegetal plate into blastocoel. Although morphological and molecular events have been well studied for gastrulation, the mechanical driving forces and their regulatory mechanism underlying the gastrulation is not fully understood. In this study, structural features and cytoskeletal distributions were studied in sea urchin embryo using an "exogastrulation" model induced by inhibiting the H+/K+ ion pump with omeprazole. The vegetal pole sides of the exogastrulating embryos had reduced roundness indices, intracellular pH polarization, and intracellular F-actin polarization at the pre-early gastrulation compared with the normal embryo. Gastrulation stopped when F-actin polymerization or degradation was inhibited by RhoA or YAP1 knockout, although pH distributions were independent of such a knockout. A mathematical model of sea urchin embryos at the early gastrulation reproduced the shapes of both normal and exogastrulating embryos using cell-dependent cytoskeletal features based on F-actin and pH distributions. Thus, gastrulation required appropriate cell position-dependent intracellular F-actin distributions regulated by the H+/K+ ion pump through pH control.

Tumor Reversion: Mesenchymal-Epithelial Transition as a Critical Step in Managing the Tumor-Microenvironment Cross-Talk

2017 ◽  
Vol 23 (32) ◽  
pp. 4705-4715 ◽  
Author(s):  
Mariano Bizzarri ◽  
Alessandra Cucina ◽  
Sara Proietti
Keyword(s):  
Conformational Changes ◽  
Cross Talk ◽  
Regulation Of Gene Expression ◽  
Pharmacological Intervention ◽  
Molecular Events ◽  
Wide Range ◽  
Cancer Types ◽  
Mesenchymal Epithelial Transition

Tumour reversion represents a promising field of investigation. The occurrence of cancer reversion both in vitro and in vivo has been ascertained by an increasing number of reports. The reverting process may be triggered in a wide range of different cancer types by both molecular and physical cues. This process encompasses mandatorily a change in the cell-stroma interactions, leading to profound modification in tissue architecture. Indeed, cancer reversion may be obtained by only resetting the overall burden of biophysical cues acting on the cell-stroma system, thus indicating that conformational changes induced by cell shape and cytoskeleton remodelling trigger downstream the cascade of molecular events required for phenotypic reversion. Ultimately, epigenetic regulation of gene expression (chiefly involving presenilin-1 and translationally controlled tumour protein) and modulation of a few critical biochemical pathways trigger the mesenchymal-epithelial transition, deemed to be a stable cancer reversion. As cancer can be successfully ‘reprogrammed’ by modifying the dynamical cross-talk with its microenvironment thus the cell-stroma interactions must be recognized as targets for pharmacological intervention. Yet, understanding cancer reversion remains challenging and refinement in modelling such processes in vitro as well as in vivo is urgently warranted. This new approach bears huge implications, from both a theoretical and clinical perspective, as it may facilitate the design of a novel anticancer strategy focused on mimicking or activating the tumour reversion pathway.

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