Sunday, June 1, 2025
6/1/2025
Regulation of cell growth and proliferation by the Hippo pathway - PROJECT SUMMARY/ABSTRACT Precise regulation of cell growth and proliferation is necessary to maintain tissue homeostasis and organ size, and this regulation is predominantly controlled by two highly conserved signaling pathways: the Hippo and mammalian target of rapamycin (mTOR) pathways. Deregulation of the Hippo and/or mTOR pathways cause tissue overgrowth phenotypes that are well known to contribute to human disease. Understanding how the Hippo and mTOR signaling pathways coordinate their activities is therefore a critically important, yet poorly understood, area of cell biology. In the last funding period, my group identified the kinase STK25 as an upstream activator of the Hippo signaling pathway that directly phosphorylates and activates the core Hippo kinases LATS1 and LATS2 to induce cell cycle arrest. We have now generated strong preliminary data indicating that activation of STK25 also functions to dampen mTORC1 signaling, both in vitro and in vivo. However, the mechanism by which STK25 regulates mTORC1 is unknown. The goal of this proposal is to combine cell biology, biochemistry, CRISPR-screening, and animal model methodologies to test our overarching hypothesis that the kinase activity of STK25 plays a critical role in coordinating the activities of both the Hippo and mTORC1 signaling pathways to regulate cell growth and tissue homeostasis. In Aim 1, we will use unbiased chemical-genetic and phospho- proteomic approaches to identify STK25 substrates and define the molecular mechanisms through which STK25 negatively regulates mTORC1 activity. In Aim 2, we will define how STK25 kinase activity is regulated, and use a conditional STK25 knockout mouse model we have recently developed to determine the phenotypic consequences of STK25 gene deletion on cell growth and proliferation in vivo. In Aim 3, we will use an innovative gain-of-function CRISPRa-based screen to identify new regulators of the Hippo pathway, both in vitro and in vivo. Successful completion of these aims will illuminate fundamental principles as to how the Hippo and mTORC1 signaling pathways coordinate their activities to maintain tissue homeostasis and provide new insights into how these pathways are deregulated in human disease.
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