The response of cells to mechanical inputs is a key determinant of cell behavior. In response to changes in the mechanical environment of epithelial cells, E-cadherin initiates signal transduction cascades that allow the cells to modulate their contractility to withstand the force. Much attention has focused on identifying the E-cadherin signaling pathways that promote contractility, but the negative regulators remain undefined. In this thesis, we identify SHP2 as a force-activated phosphatase that negatively regulates E-cadherin force transmission by dephosphorylating vinculin Y822. To specifically probe a role for SHP2 in E-cadherin mechanotransduction, we innovatively mutated vinculin so that it retains its phosphorylation but cannot be dephosphorylated. Cells expressing the mutant vinculins have increased contractility. This work provides the first mechanism for inactivating E-cadherin mechanotransduction and provides a new method for specifically targeting the action of phosphatases in cells.
Dissertation
Shp2 is activated in response to force on E-cadherin and dephosphorylates vinculin Y822
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2018
DOI: 10.17077/etd.ur0eexl7
Abstract
Details
- Title: Subtitle
- Shp2 is activated in response to force on E-cadherin and dephosphorylates vinculin Y822
- Creators
- Christy Rose Heidema - University of Iowa
- Contributors
- Kris A. DeMali (Advisor)John G. Koland (Committee Member)Dawn E. Quelle (Committee Member)Mark A. Stamnes (Committee Member)Tina L. Tootle (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Molecular and Cellular Biology
- Date degree season
- Spring 2018
- DOI
- 10.17077/etd.ur0eexl7
- Publisher
- University of Iowa
- Number of pages
- xvii, 161 pages
- Copyright
- Copyright © 2018 Christy Rose Heidema
- Language
- English
- Date submitted
- 09/05/2018
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
All cells are subjected to mechanical forces throughout their lifetimes. An example of the forces our cells experience is demonstrated by epithelial cells that line ducts or the endothelial cells that line blood vessels. These cells are constantly subjected to mechanical forces, including shear stress due to fluid flow, hydrostatic pressure, osmotic force, and stretching and compressive forces. As a result, cells need a structure and mechanism to be able to sense and respond to force.
This function is served by cell-surface adhesion receptors, which allow cells to respond to force in a coordinated manner. This thesis focuses on the cadherin adhesion receptors, which link cells to one another. In response to force, cadherins mediate a cell stiffening response, which involves increases in internal cellular contractility and growth of the adhesion complexes. However, cells must also modulate their stiffness to maintain a balance of forces between the cell and its environment. This process requires a precise balance of force-promoting and force-inhibiting processes.
In this thesis, we identify a novel, negative regulator of cadherin force transduction—SHP-2. SHP-2 inhibits force transduction by removing a phosphate group from vinculin—a key component of cadherin force transmission. In doing so, SHP-2 allows the cell to alleviate its stiffening response. In sum, this work describes a novel mechanism regulating force transmission within a cellular context.
- Academic Unit
- Interdisciplinary Graduate Program in Molecular Medicine
- Record Identifier
- 9983777299902771
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