Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

Summer 9-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Yina Huang

Abstract

Immune surveillance requires efficient trafficking of leukocytes throughout the body. To achieve this, leukocytes have evolved to be highly migratory and responsive to environmental cues, which provide guidance for proper tissue distribution. The translation of external environmental cues to intracellular physical changes in leukocytes requires a cascade of receptors, signal transducers, and mechanical effectors. My doctoral research focused on using T-cells as a model to study the unique cellular process of how signal transducers interact with and regulate mechanical effectors in fast migrating immune cells. Specifically, it is known that the signal transducer Mst1 kinase is required for T-cell polarization, adhesion, and active migration, but the underlying mechanisms remain poorly understood. I have demonstrated that Mst1 regulates two mechanical effectors, the molecular motor Myosin-IIA and the cytoskeleton regulatory protein L-plastin, through the process of phosphorylation. Theregulation of Myosin-IIA enables it to generate contractile force inside a migrating T-cell, maintaining the shape and proper adhesion of the cell to extracellular matrix, both being requirements for successful migration. The regulation of L-plastin enables it to activate integrin adhesion molecules as well as to properly organize lamellipodial actin. In addition, I have identified novel adhesion structures in T-cells called microadhesions, which potentially provide traction force to migrating T-cells. Overall, my research has identified a novel pathway acting between a signal transducer and two mechanical effectors in T-cell migration.

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K7B8565Q

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