Coordinated Cytoskeletal Dynamics and Membrane Remodeling in Cellular Shape Change

PROJECT SUMMARY TRIM9 and TRIM67 are brain- and cancer-enriched E3 ubiquitin ligases implicated in neurodevelopment, neuronal function and maintenance, and cancer. The overarching long-term goal of this research program is to define how TRIM9 and TRIM67 promote cellular shape change in developing neurons and migrating melanoma. Specifically, we are studying shape change in the context of neuronal morphogenesis and function, and melanoma cell motility and metastasis. TRIM9 and TRIM67 are situated at the interface of receptors for the extracellular guidance cue netrin, cytoskeletal remodeling proteins, and membrane trafficking proteins. The amalgamation of our published, preprinted, and preliminary data indicates that TRIM9 and TRIM67 are potent regulators of the cytoskeleton, membrane remodeling in response to netrin. We hypothesize these functions converge upon the diverse cell shape changes in developing neurons and migrating melanoma. Our studies support the hypothesis that the ligases function via nondegradative ubiquitination, a vastly understudied post- translational modification. More work is needed to confirm the broad relevance of this modification and to define the mechanisms by which TRIM9 and TRIM67 function in neurons and in melanoma. The uniqueness and conceptual innovation of this research program includes investigating brain-enriched E3 ubiquitin ligases in neurons and cancer, discovering nondegradative functions of ubiquitin that provide rapid, reversible regulation, and identifying mechanisms connecting netrin receptors to diverse cellular shape changes. We will continue to exploit TRIM9 and TRIM67 as a handle to define mechanisms of cellular shape change in developing neurons and migrating melanoma. Overarching questions and hypotheses are presented in themes of regulation of A) the cytoskeleton and adhesion, B) membrane remodeling, and C) receptors and signaling pathways. .