Monday, May 6, 2024
5/6/2024
PROJECT SUMMARY Wnt signaling is an evolutionarily conserved pathway that regulates several cellular behaviors such as cell proliferation, survival, differentiation, and migration to promote tissue homeostasis. Of note, the Wg/Wnt signaling pathway is important for tissue patterning and is often deregulated in epithelial cancers. Secreted Wnt ligands are distributed in the extracellular space to promote paracrine and long-range signaling in target cells. These paracrine and long-range functions of Wnts are dependent on extracellular Wnt availability, which in part is dictated by cell-surface glypican, Dally-like protein (Dlp). In this proposal, I will focus on molecular mechanisms that dictate Dlp-mediated regulation of Wnt availability and signaling. Dlp’s role in regulating Wnt signaling has been described as ‘biphasic’: By continual binding and release, Dlp simultaneously promotes long-range signaling and restricts paracrine signaling, ensuring proper ligand availability at both ranges. The Page-McCaw lab established Drosophila germarium, a tissue where oogenesis occurs, as a model to study mechanisms that define Wnt signaling ranges, and identified a novel Dlp/Mmp2 (Matrix Metalloprotease 2) module that modulates paracrine and long-range Wnt signaling in the germarium. Specifically, I found that proteolytic cleavage of Dlp by Mmp2 alters its subcellular localization and function to modulate Wnt availability. Additionally, my preliminary data suggest that Dlp/Mmp2 may regulate Wnt signaling in epithelial tumors to promote tumor growth. In Aim 1, I will investigate the molecular events that occur downstream of proteolytic cleavage of Dlp to modulate Wg/Wnt availability and signaling in the germarium and tumors. The extracellular Wnt distribution is tightly linked with its production and secretion. I found that Dlp can modulate Wg (Wnt-1) production in source cells in the germarium. Wg production in source cells in germaria is tightly regulated and this regulation is crucial for proper oogenesis. Additionally, I found that Dlp interacts with non-ligand proteins (a finding that has not been previously reported) that communicate with intracellular cytoskeletal machinery, potentially to modulate cell adhesion and/or shape. In Aim 2, I will investigate novel mechanisms of how Dlp regulates Wnt ligand production and long-range Wg distribution to facilitate long-range Wg signaling. These investigations will uncover previously unappreciated roles of cell-surface glypicans in regulating Wnt signaling and elucidate novel paradigms of developmental strategies employed in multicellular organisms to maintain tissue homeostasis.
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