Coordinated Cytoskeletal Dynamics and Membrane Remodeling in Cellular Shape Change

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PROGRAM DESCRIPTION The overarching research goal of my lab is to define cellular and molecular mechanisms mediating cellular shape change. Cellular shape change is a fundamental characteristic of metazoan cells, key to development, physiology, and pathology. The formation and plasticity of neural networks are key examples of cell shape change during development and physiology, whereas cell shape and motility goes awry in pathological conditions, such as melanoma. We study two main themes during cellular shape change: The active control of the cytoskeleton, which is acknowledged as critical to cellular shape change, and the concurrent remodeling of the plasma membrane, which is perhaps less well appreciated. Although many cytoskeletal and membrane remodeling components are known and their biochemical and structural characteristics described, we lack a systematic understanding of how these disparate systems are regulated and coordinated to orchestrate cellular shape change. Perhaps the most important problem in cell morphogenesis is understanding how cells perceive cues in their environment and convert this extracellular information into shape changes through coordinated cytoskeletal dynamics and plasma membrane remodeling; this is the focus of this proposal. Functions of small GTPases and kinases have been extensively studied in regulating cytoskeletal dynamics and membrane remodeling. Work from my lab identified an emerging role for E3 ubiquitin ligases in regulated cellular shape change. We identified two E3 ubiquitin ligases, TRIM9 and TRIM67, which regulate cytoskeletal and exocytic proteins and cellular shape changes in response to netrin. The extracellular morphogen netrin promotes neuronal morphogenesis and cancer progression. Despite these important consequences, we know little about how cells interpret netrin into shape changes. TRIM9 and TRIM67 provide an excellent opportunity to investigate the function of ubiquitination in cytoskeletal and membrane remodeling, and how these functions are coordinated during netrin triggered cell shape change and motility. TRIM9 and TRIM67 share similar sequences, localization, and interaction partners, however our studies identified distinct functions of these related proteins and antagonistic phenotypes associated with their deletion. The overarching goal of this program is to test the hypothesis that TRIM9 and TRIM67 coordinate cytoskeletal dynamics and exocytosis during netrin-dependent morphogenesis in multiple cell types. Since netrin plays roles in both neuronal development and cancer pathogenesis, our work will exploit developing neurons and migrating melanoma cells as model systems. Our preliminary and published data indicate both cell types respond to netrin and express TRIM9 and TRIM67. Our work will illuminate fundamental generalities and cell type specific mechanisms of shape change, providing mechanistic understanding of the coordination of the cytoskeleton and membrane trafficking during development and metastasis.