Dynamic Cortical Mechanotransduction Drives Rounded Cell Protrusions Public Deposited

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  • March 22, 2019
Creator
  • Costigliola, J. Nancy
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • As cells decrease their area of attachment, as occurs in 3D migration, F-actin is remodeled from integrin-dependent, relatively flat networks to a contractile cortex located at the rounded cell periphery. Concurrently, as the area of attachment decreases, dependence on myosin II contractility for cell motility increases (Doyle et al., 2009; Friedl and Wolf, 2010). I investigated the dynamic behavior and regulation of actomyosin-driven periodic protrusions in rounded fibroblast and endothelial cells. Because this contractile behavior is periodic, the regulation of the contractility must be due to negative and, possibly also positive, feedbacks. To that end I investigated two major regulatory pathways of myosin II contractility, Calcium and the small GTPase RhoA. Although Calcium is known to govern periodic contractility and signaling in other systems (Berchtold et al., 2000; Chen et al., 2009; Katz and Repke, 1966; Kruskal and Maxfield, 1987; Lee et al., 1999; Marks and Maxfield, 1990; Somlyo and Somlyo, 2003)and had been previously implicated in our system by both theoretical and experimental evidence(Kapustina et al., 2008; Pletjushkina et al., 2001; Salbreux et al., 2007; Weinreb et al., 2006; Weinreb et al., 2009), I found no evidence of periodic calcium release governing myosin activity in these protrusions. Rather, I found that RhoA activity exhibited spatiotemporal oscillatory behavior. RhoA activity, co-localized with the actin cortex, traveled in waves, and was necessary for periodic protrusions. By investigating the regulation of these waves, I found evidence that the waves are regulated by a positive feedback loop at the cortex from myosin II, which is downstream of RhoA, to GEFH1, which is upstream of RhoA. Further, this positive feedback of the RhoA pathway reveals a novel form of cortical mechanotransduction that occurs independently of integrin-mediated signaling, a property that could be useful for cells migrating with reduced substrate affinity in 3D environments.
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  • In Copyright
Advisor
  • Jacobson, Ken
Degree
  • Doctor of Philosophy
Graduation year
  • 2012
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