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Vimentin Cytoskeleton Collapses in Response to the Small Molecule Inhibitor of FH2 Domains (SMIFH2)-Induced Electrophilic Stress
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Spring 2026
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2026-01
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Elevated levels of vimentin are detectable in cancerous tissue from malignant neoplasms as well as fibrotic tissue. Vimentin constitutes one of the polymer-based components of the cytoskeleton that regulates cellular morphology and promotes effective and efficient cellular migration and motility. These aspects of cellular behavior contribute to the homeostatic repair of tissue, as evidenced by the trafficking of immune cells and fibroblasts to the lesion site, as well as the progression of pathological conditions, as demonstrated by the invasion of tumor cells through the stromal matrix. Within the cell, the vimentin cytoskeletal network serves as a viscoelastic, load-bearing scaffold that surrounds the nucleus and radiates throughout the cell. Through direct and/or indirect interactions, the vimentin cytoskeleton bidirectionally communicates with the actin and microtubule cytoskeletal networks. To date, the formin family of actin-modifying proteins have not been implicated as mediators of crosstalk between the actin and vimentin cytoskeletal networks. However, recent work in our lab has demonstrated that treatment with the small-molecule inhibitor of formin homology 2 domains (SMIFH2) disrupts vimentin organization and collapses the network to the perinuclear region of the cell. However, this inhibitor has also been found to affect other proteins and cellular pathways independent of formin function. Therefore, potentially uncovering a connection between formins and the vimentin cytoskeleton or discovering the off-target, formin-independent, mechanism that SMIFH2 collapses the vimentin network warrants interest as a necessary research direction in order to expand the area of vimentin-related biomedical research. The work presented in Chapter 2 of this dissertation presents sufficient evidence that the disruptive effect SMIFH2 induces on the vimentin cytoskeleton is the result of the inhibitor's electrophilic characteristic and not formin-dependent inhibition. Importantly, we have shown that formin depletion, actin cytoskeleton disruption, or potential off-target inhibition of actomyosin contractility do not disrupt the vimentin cytoskeleton in a manner similar to SMIFH2 treatment. SMIFH2 exerts its electrophilic effect directly onto vimentin and interferes with network dynamics. These findings, as well as the general discussion in Chapter 3, address whether formins regulate vimentin organization, but also highlight the need to further refine and develop more specific cellular manipulations in order to limit unintended, off-target effects of drugs and therapeutics.
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