Quantitative Analysis of Integrin Trafficking and Focal Adhesion Turnover to Study Integration of Early Endocytic Trafficking, Signaling and Migration




Lakoduk, Ashley Marie

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Early endocytic trafficking is critical for regulating both receptor presence at the plasma membrane and cellular signaling. Clathrin-mediated endocytosis (CME) constitutes a major route of selective receptor internalization, yet little is knowing about how this process is regulated both temporally and spatially. We chose to investigate focal adhesion (FA) and beta-1 integrin turnover as a model system to better understand the spatial, temporal, and cargo-specific regulation of early endocytic trafficking. Importantly, the dynamic turnover of integrins and their associated adhesion complexes through endocytic and recycling pathways has emerged as key mechanism for controlling cancer cell migration and invasion. However, current tools available to study integrin trafficking do not provide adequate spatial information or can induce artifacts. Here, we report the generation and characterization of a neutral and monovalent antibody-based probe to study beta-1 integrin trafficking in cells. Using this tool, we report a novel regulatory mechanism of integrin turnover by a lipid kinase, PIPKI, and discover a mutant p53-driven endosomal signaling nexus that regulates beta-1 integrin recycling and cancer cell invasion. This work demonstrates the importance of the reciprocal crosstalk between early endocytic trafficking and receptor signaling in regulating both normal and tumor cell function.

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Pages 8-153 are misnumbered as pages 9-154.

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