The ability of cells to alter their shape is critical to the ontogeny of most organisms. Within tissues, for example, changes in cellular morphology drive tissue remodeling during morphogenesis and are essential for wound repair. At the level of the individual cell, cycles of shape change allow some cell types to migrate during embryogenesis, immune function, and (more insidiously) during metastasis. Cellular morphology is dictated by the cytoskeleton - the network of actin filaments and microtubules. The long-term goal of this project is to understand the principles and mechanisms underlying cellular morphology at the molecular level by studying the pathways that regulate and integrate cytoskeletal dynamics. Importantly, the networks of actin and microtubules do not act in isolation, rather there is an unprecedented degree of cross-talk, both regulatory interactions and mechanical interactions. Microtubule plus end-tracking proteins (or +TIPs) are a class of molecules that selectively localize to the tips of growing and shrinking microtubules. Since their discovery in 1999, +TIPs have been implicated in almost every microtubule-dependent cellular function including regulation of microtubule dynamic instability, organelle and chromosomal transport, assembly of the mitotic spindle, establishment of cellular polarity, and cell migration. In this proposal, we focus on +TIPs with a particular emphasis on actin-microtubule cross-talk as this represents a relatively unexplored functional interface between the two cytoskeletal networks. Our core hypothesis is that microtubule plus ends are dynamic platforms that deliver information to cortical regulatory networks governing cell shape and also act as sites of structural integration between actin and microtubules. We will test these ideas using novel assays we have developed with cultured Drosophila cell lines as this model system is amenable to high-resolution light microscopy, biochemical analyses, and gene inhibition using RNAi. The results of these studies will contribute to a basic understanding about the network of cellular components that mediate changes in cellular shape during processes such as morphogenesis and cell migration. The goal of this proposal is to understand the mechanistic basis of cellular morphogenesis and motility. The proper execution of cellular shape changes is essential for embryonic development - if they are not synchronized during development, or fail to occur at all, this can result in congenital birth defects. Like wise, cellular motility underlies processes such as wound healing and immune response. Improper cell motility is also an underlying cause of atherosclerosis, inflammation, and metastasis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Structure and Function (CSF)
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Deatherage, James F
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Grode, Kyle D; Rogers, Stephen L (2015) The non-catalytic domains of Drosophila katanin regulate its abundance and microtubule-disassembly activity. PLoS One 10:e0123912
Trogden, Kathryn P; Rogers, Stephen L (2015) TOG Proteins Are Spatially Regulated by Rac-GSK3? to Control Interphase Microtubule Dynamics. PLoS One 10:e0138966
Montgomery, Ellyn R; Temple, Brenda R S; Peters, Kimberly A et al. (2014) G?12 structural determinants of Hsp90 interaction are necessary for serum response element-mediated transcriptional activation. Mol Pharmacol 85:586-97
Manning, Alyssa J; Peters, Kimberly A; Peifer, Mark et al. (2013) Regulation of epithelial morphogenesis by the G protein-coupled receptor mist and its ligand fog. Sci Signal 6:ra98
Peters, Kimberly A; Rogers, Stephen L (2013) Drosophila Ric-8 interacts with the G?12/13 subunit, Concertina, during activation of the Folded gastrulation pathway. Mol Biol Cell 24:3460-71
Leano, Jonathan B; Rogers, Stephen L; Slep, Kevin C (2013) A cryptic TOG domain with a distinct architecture underlies CLASP-dependent bipolar spindle formation. Structure 21:939-50
Applewhite, Derek A; Grode, Kyle D; Duncan, Mara C et al. (2013) The actin-microtubule cross-linking activity of Drosophila Short stop is regulated by intramolecular inhibition. Mol Biol Cell 24:2885-93
Currie, Joshua D; Stewman, Shannon; Schimizzi, Gregory et al. (2011) The microtubule lattice and plus-end association of Drosophila Mini spindles is spatially regulated to fine-tune microtubule dynamics. Mol Biol Cell 22:4343-61
Zhang, Dong; Grode, Kyle D; Stewman, Shannon F et al. (2011) Drosophila katanin is a microtubule depolymerase that regulates cortical-microtubule plus-end interactions and cell migration. Nat Cell Biol 13:361-70
Currie, Joshua D; Rogers, Stephen L (2011) Using the Drosophila melanogaster D17-c3 cell culture system to study cell motility. Nat Protoc 6:1632-41

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