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Chemical Tools for Investigating Galectin Dynamics

  • Author(s): Belardi, Brian
  • Advisor(s): Bertozzi, Carolyn R.
  • et al.
Abstract

Pattern recognition is an essential feature governing many biological processes, including metazoan development, infection, and tumorigenesis. Glycans form a unique pattern on the surfaces of cells. There, these branched, intricate structures are poised to direct communication between neighboring cells and tissues. How cells interpret the staggering complexity associated with the glycome, the repertoire of glycan structures expressed in cells and tissues, though is still not well understood. Galectins comprise one family of glycan-binding proteins that are thought to play a role in decoding glycomic patterns. They have been implicated in cell adhesion and signaling, proliferation, membrane organization, and transcript processing. Yet, the mechanistic underpinnings of the pleiotropic functions of galectins remain obscure due to challenges associated with studying lectin-glycan interactions.

Monitoring and modulating glycan patterns present on different cell surface glycoconjugates would greatly facilitate our understanding of galectin-dependent phenomena. Unfortunately, glycosylation is a post-translational modification that is dependent on the collective action of hundreds of enzymes. The final glycans appended to proteins and lipids are not directly encoded in the genome, and as such, there is no obvious means to tag or tailor complex, galectin ligands in vivo. This situation is further exacerbated by the properties of galectins themselves. Galectin-1, for instance, self-assembles in vitro and traverses cell membranes, occupying extracellular, cytosolic, and nuclear spaces. Therefore, isolating galectins' dynamic organization in each subcellular context is imperative, yet non-trivial experimentally.

This dissertation describes the development of new chemical and biophysical tools for studying galectin dynamics and their contribution to cellular physiology and pathology. Chapter 1 explores and summarizes recent advances in chemical methodology that report on mammalian lectin function in vivo. In Chapters 2 and 3, I present a platform for monitoring galectin-mediated cross-linking on living cells with synthetic glycoprotein mimics. Chapter 4 outlines a technique to image galectin ligands, i.e. specific protein glycoforms, in cultured cells and tissue slices. Finally, Chapter 5 is dedicated to clarifying galectin's influence on mammary gland morphogenesis and breast cancer progression. Therein, I discuss harnessing the tools described in Chapters 1-4 to reveal an unprecedented, galectin-based mode of information transfer between extracellular glycomic signatures and nuclear transcription machinery that drives mammary epithelial invasion.

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