Probing molecular and cellular design principles in signaling : from Wnt biology to cytoskeletal mechanics
Abstract/Contents
- Abstract
- Most animals develop from a single-celled embryo into a morphologically complex adult form through a coordinated program of cell division, migration, death and differentiation. This developmental process is guided in large by mechanical and biochemical signals. The same signaling pathways are involved in the normal functioning of a grown adult, and their malfunction enables pathologies such as cancer and pathogenic infection. In this thesis, I focus on understanding how a subset of these pathways allow cells to communicate and interact with extracellular signals at a molecular and cellular level. In Chapter I, we investigated mechanisms by which the developmental signaling protein Wnt activates the canonical Wnt pathway, where the cell is instructed to turn off the "destruction complex" constitutively inhibiting the main co-transcriptional activator of the pathway. We find that upon Wnt activation, Dishevelled, the cytoplasmic transducer of the Wnt signal, is mostly present as oligomers of 1 to 10 molecules. The oligomers possess a double helical filamentous nature, and likely recruit and inhibit the destruction complex component protein Axin at the filament ends, thus enabling Wnt activation. In Chapter II, we study mechanisms by which epithelia respond to mechanical challenges, a critical part of their physiological role. In particular, we ask how cells recover when a wound forces them to detach from their adhesions. We find that branched actin polymerization-based lamellipodial membrane spreading helps recover the cell's original footprint within seconds, which is closely guided by membrane tethers extruded from adhesions during the detachment. Our experiments suggest that extruded tether-guided lamellipodia constitute a robust and general wound-healing response to cell detachment. In Chapter III, we focus on the cytoskeletal actin cortex beneath the cell membrane, which mechanically supports the cell but is able to drive processes such as cell migration through rapid remodeling. We ask how the cortex can be dynamic within the plane of the membrane, while simultaneously maintaining a stable attachment to the membrane through membrane-cortex linker proteins. By developing an optical trap assay, we show that the stereotypical membrane-cortex linker protein Ezrin forms a complex of 2-3 molecules that behave as a sliding anchor over micron distances while resisting orthogonal detachment forces. We propose that sliding anchors may constitute an overlooked yet essential element of the cell cortex.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Korkmazhan, Elgin |
|---|---|
| Degree supervisor | Dunn, Alexander Robert |
| Thesis advisor | Dunn, Alexander Robert |
| Thesis advisor | Bryant, Zev David |
| Thesis advisor | Fordyce, Polly |
| Thesis advisor | Weis, William I |
| Degree committee member | Bryant, Zev David |
| Degree committee member | Fordyce, Polly |
| Degree committee member | Weis, William I |
| Associated with | Stanford University, Biophysics Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Elgin Korkmazhan. |
|---|---|
| Note | Submitted to the Biophysics Program. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/kz486mq7639 |
Access conditions
- Copyright
- © 2022 by Elgin Korkmazhan
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