Sunday, November 24, 2024
11/24/2024
DESCRIPTION (provided by applicant): Contact inhibition limits cell growth in tissues, but is highly subject to regulation. It can be overcome in rapidly growing tissues during development, regeneration, and wound healing. Contact inhibition is frequently lost in tumor cells, allowing tumors to grow well beyond their normal tissue constraints. The mechanisms underlying contact inhibition are poorly understood, but cadherin-mediated cell-cell adhesion is thought to play an important role. We have shown that homophilic adhesive binding between E-cadherin proteins at the cell surface, in association with catenins bound to their cytoplasmic domains, directly mediate contact inhibition of growth. We've found that cadherin-catenin mediated contact inhibition occurs via two major pathways; inhibition of growth factor receptor signaling, which we now find results from inhibition of Src family kinases (SFKs); and our preliminary findings also implicate the Hippo signaling pathway, in particular the nuclear localization of the Hippo pathway transcriptional mediator YAP. The Hippo pathway was originally discovered as a regulator of organ size in Drosophila embryos, and recently has been shown to regulate mammalian cell growth, contact inhibition, and tumor development. We have made another novel preliminary finding that growth factor signaling and SFK activity affect YAP nuclear localization and function in some cells, suggesting another important mechanism of Hippo pathway regulation. The overall hypothesis is that E-cadherin-catenin regulates contact inhibition of growth both by stimulating the Hippo signaling pathway and by inhibiting src family kinase (SFK) activity, and in this way it serves to coordinate or balance growth inhibitory signaling with the mitogenic signaling by growth factor receptors. We will first investigate the functional and physiological relationships between E-cadherin-2-catenin mediate adhesion, Hippo pathway signaling, SFK signaling, and Epidermal Growth Factor Receptor (EGFR) signaling. We will determine the molecular mechanisms by which these pathways regulate each other in cell culture models and then test their importance in vivo for tumor formation and normal tissue development in mice. The specific aims are: A. Elucidate the mechanism(s) by which homophilic binding between E-cadherin-catenin complexes regulates signaling through the Hippo pathway. B. Determine how EGFR and SFK signaling regulate the nuclear localization and function of the Hippo pathway transcriptional activator YAP, understand the role of Hippo pathway-mediated growth inhibition in the regulation of mitogenic signaling by EGFR and SFKs, and elucidate the mechanism(s) of regulation SFK activity by E-cadherin-catenin adhesive complexes. C. Evaluate the roles of E-cadherin-catenin-mediated contact inhibition and Hippo pathway signaling in the development of mammary glands and mammary tumors in vivo in mice, and their roles in tumorigenesis driven by Receptor Tyrosine Kinase (RTK) and SFK signaling pathways. Findings from these studies should reveal how contact inhibition regulates normal tissue development and how the loss of contact inhibition leads to the formation and progression of tumors.
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