The Role of GEF-H1 in the Regulation of the Hippo Pathway
Year: 2025
Type: dissertation
Abstract: Microtubules are large and dynamic structures that regulate intracellular signaling, acting as scaffolds for various kinases, phosphatases, and adaptor proteins. Local changes in microtubule stability can modulate these pathways, leading to biologically and clinically relevant changes in cell behaviour. Previous research has shown that microtubule depolymerization potently activates the transcription factor YAP, which is normally maintained in an inactive state through the activity of the Hippo pathway. GEF-H1 is a microtubule-associate protein which acts as a guanine nuclear exchange factor (GEF) for RhoA, a small GTPase which regulates actin and microtubule dynamics. GEF-H1 associates with microtubules in an inactive state, and microtubule depolymerization results in its activation. Here, I identify GEF-H1 as a key mediator linking microtubule depolymerization to integrin signaling and the Hippo pathway. Specifically, GEF-H1 binds to and activates the small GTPase RhoA via its catalytic GEF activity, and downstream activation of RhoA is necessary for YAP dephosphorylation. FAK is also activated by microtubule depolymerization through a GEF-H1-dependent mechanisms. Pharmacologic inhibition of FAK attenuates YAP activation in nocodazole-treated cells, suggesting that FAK contributes to the activation of YAP by microtubule depolymerization. GEF-H1 interacts with and inhibits MAP4K4, a negative regulator of both FAK signaling and YAP/TAZ activity. These findings reveal a novel mechanism by which microtubule dynamics regulate YAP activation, integrating cytoskeletal changes with mechanotransduction and Hippo signaling. By elucidating the molecular connections between microtubules, RhoA signaling, and YAP/TAZ regulation, this work provides new insights into how cells coordinate biochemical and mechanical inputs to control their behavior.
Source: TSpace (University of Toronto)
Author: Cowen, Justin Gabriel
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7133035180