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Lauren V. Albrecht, Ph.D., AP Giannini Postdoctoral Scholar, Biological Chemistry, University of California Los Angeles

Methylation Links Metabolism and Growth through Wnt Signaling

In this presentation, I will tell the story of my work that explores a general phenomenon whereby growth factors co-opt proteolytic pathways to fuel growth, using the Wnt pathway as a specific experimental paradigm. Physiologically, the Wnt pathway plays a vital role in growth; pathologically, Wnt signaling contributes to the development of cancer. Despite being the focus of intensive research over the past twenty years, how Wnt signaling promotes cancer cell growth has remained mysterious. We found that Wnt signaling hijacks lysosomes in order to replenish free metabolites for new protein synthesis, growth, and expansion. Originally thought to solely operate as the “garbage can” of the cell, lysosomes have emerged as a central metabolic signaling hub. In line with this, my work showing that growth factors orchestrate lysosomal degradation dispels the classic dogma that these organelles simply provide a janitorial service for the cell and illuminates novel vulnerabilities for targeting growth in cancer. My work studying the nature of lysosomal delivery unexpectedly revealed a novel mechanism for protein degradation in eukaryotes, hitherto unappreciated. This serendipitous finding was sparked by an initial observation that growth factors increased not only lysosome activity, but also sheer lysosome size by ten- fold, within minutes. The constituents of massively engorged lysosomes included a diverse repertoire of seemingly random proteins. However, after closer investigation, we realized that the proteins captured within lysosomes had one key factor in common – they were all methylated, within a signature motif, similar to protein ubiquitination. I found that this novel methylation tag drove the tumor suppressor, Smad4, into lysosomes in order to promote TGF-ß signaling. Similarly, my work revealed that through the methylation of key players in the Wnt pathway were essential for ß-catenin activity, and offered a new approach to decrease aberrant Wnt signaling in cancer. These findings herald a new era of research by establishing an unforeseen, widespread mechanism for protein degradation with implications in genetic disease and cancer.

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