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Pharmacology and Molecular Sciences
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Cytokinesis and Cell Shape Control
Multi-cellular living organisms grow from single cells into multicellular, complex systems composed of highly diverse cell-types organized into tissues, which in turn form organs and organ systems. To organize and maintain this complex architecture, the organism must undergo constant renewal through cell proliferation and elimination of unwanted cells. This process of tissue development and homeostasis requires chemical and mechanical information to be sensed by the cells within the tissues, and in turn, interpreted to guide their decision making: to divide, migrate, constrict, or die. Failure in these processes lead to diverse diseases, such as hypertension, degeneration, and cancer. We have been studying cytokinesis (cell division) as a model cell behavior that incorporates internally generated signals with external mechanical cues to drive healthy cell shape change. We have discerned the mechanics that drive this process, and identified how the cell senses external forces (mechanosensing) and transmits them to changes in the chemical signaling pathways that guide cytokinesis. While we continue to study how these processes direct cytokinesis, we are also learning how these same principles apply to diseases such as cancer. For example, we have identified how mechanical cues guide aberrant behaviors in breast cancer. In this case, we found that cancer and non-cancer cells compete with each other, and due to their unique mechanical properties, the cancer cell can engulf and kill the non-cancer cell. In another project, we are exploring how cellular growth control pathways lead to defects in cell mechanics. In particular, a key regulatory pathway, which guides liver formation and leads to liver cancer if the pathway becomes uncontrolled, also controls the hepatocyte mechanical properties. Finally, we have found that these same principles apply to the development of a mammalian egg where disruption of the cell mechanics machinery causes defects in the formation of a healthy egg. Such mechanics defects could contribute to some types of human infertility and/or birth defects.
Luo T, Mohan K, Iglesias PA, Robinson DN. Molecular mechanisms of cellular mechanosensing. Nat. Mater. 2013; 12: 1064-1071.
Sun Q, Luo T, Ren Y, Florey O, Shirasawa S, Sasazuki T, Robinson DN, Overholtzer M. Competition between human cells by entosis. Cell Res. 2014; 24: 1299-1310.
Ren Y, West-Foyle H, Surcel A, Miller C, Robinson DN*. Genetic suppression of a phosphomimic myosin II identifies system-level factors promoting myosin II cleavage furrow accumulation. Mol. Biol. Cell 2014; 25: 4150-4165.
Surcel A, Ng W-P, West-Foyle H, Zhu Q, Ren Y, Avery L, Krenc AK, Meyers D, Rock RS, Anders RA, Freel Meyers C, Robinson DN. Pharmacological activation of myosin II paralogs to correct cell mechanics defects. Proc. Natl. Acad. Sci. USA 2015; 112(5): 1428-1433.
Srivastava V, Robinson DN. Mechanical stress and network structure drive protein dynamics during cytokinesis. Curr. Biol. 2015; 25(5): 663-670.
Kim JH, Ren Y, Ng WP, Li S, Son S, Kee Y-S, Zhang S, Zhang G, Fletcher DA, Robinson DN, Chen EH. Mechanical tension drives cell membrane fusion. Dev. Cell 2015; 561-573.
Srivastava V, Iglesias PA, Robinson DN. Cytokinesis: Robust cell shape regulation. Semin. Cell Dev. Biol. 2016; 53: 39-44.
Schiffhauer ES, Luo T, Mohan K, Srivastava V, Qian X, Griffis E, Iglesias PA, Robinson DN. Mechanoaccumulative elements of the mammalian actin cytoskeleton. Curr. Biol. 2016; 26: 1473-1479.
Schiffhauer E, Robinson DN. Mechanochemical signaling directs cell shape change. Biophys. J. 2017; 112: 207-214.