Directional cell migration is essential for organism development, immune surveillance and wound repair, but is also associated with numerous pathologies including cardiovascular and neurodegenerative disorders as well as tumor metastasis. Paxillin is a scaffold protein that localizes to sites of cell-matrix interaction calle focal adhesions and we have previously shown that paxillin functions primarily as a hub for regulating Rho GTPase signaling to coordinate actin cytoskeleton remodeling and focal adhesion turnover to drive cell migration. Importantly, polarized trafficking of pro-migratory factors including integrins, through the secretory machinery to the cell's leading edge, is also required for efficient directional migration. However, the mechanism by which cell motility and polarized trafficking are integrated is not well understood. In this continuing application, we wil evaluate a novel role for paxillin as a fundamental regulator of the cell polarization machinery, through its ability to modulate microtubule function via control of alpha-tubulin acetylation. Specifically, we will use a combination of RNAi and mutant expression, biochemical assays, combined with fixed and real-time fluorescence imaging, to test the hypothesis that paxillin regulates microtubule acetylation via the deacetylase HDAC6 to control Golgi organization and positioning, as well as ER-Golgi-plasma membrane trafficking of proteins including integrins and the metalloproteinase MT1-MMP to regulate directional cell migration and invasion. We will examine the influence of environmental context on this signaling axis by comparing 2D with 1D/3D matrix models of cell polarity. Furthermore, these studies will be performed in both normal and cancer cells in order to identify ubiquitous versus cancer specific roles for paxillin signaling through HDAC6 in polarized trafficking and migration that, in turn, may facilitate the development of therapeutic intervention strategies for various cell migration-related disorders.
Cell migration is important for embryonic development, wound healing and immune surveillance. Disregulated migration also contributes various pathologies including cancer cell invasion and metastasis cardiovascular disease and various neurological defects. For cells to migrate efficiently they must develop front-rear polarity. However, our understanding of the signaling mechanisms coupling the basic cell migration machinery to the establishment of a polarized phenotype is incomplete. The proposed research will utilize complimentary 1D, 2D and 3D matrix model systems to explore a new role for the focal adhesion adapter protein, paxillin in the regulation of directed cell migration by coordinating microtubule acetylation and thereby the polarized trafficking and delivery of proteins to the plasma membrane.
|Goreczny, Gregory J; Forsythe, Ian J; Turner, Christopher E (2018) Hic-5 regulates fibrillar adhesion formation to control tumor extracellular matrix remodeling through interaction with tensin1. Oncogene 37:1699-1713|
|Gulvady, Anushree C; Dubois, Fatemeh; Deakin, Nicholas O et al. (2018) Hic-5 expression is a major indicator of cancer cell morphology, migration, and plasticity in three-dimensional matrices. Mol Biol Cell 29:1704-1717|
|Wang, Jing; Quach, Andy; Brasch, Megan E et al. (2017) On-command on/off switching of progenitor cell and cancer cell polarized motility and aligned morphology via a cytocompatible shape memory polymer scaffold. Biomaterials 140:150-161|
|Dubois, Fatemeh; Alpha, Kyle; Turner, Christopher E (2017) Paxillin regulates cell polarization and anterograde vesicle trafficking during cell migration. Mol Biol Cell 28:3815-3831|
|Rashid, Mamunur; Belmont, Judson; Carpenter, David et al. (2017) Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation. Development 144:4002-4014|
|Jacob, Andrew E; Amack, Jeffrey D; Turner, Christopher E (2017) Paxillin genes and actomyosin contractility regulate myotome morphogenesis in zebrafish. Dev Biol 425:70-84|
|Goreczny, G J; Ouderkirk-Pecone, J L; Olson, E C et al. (2017) Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene 36:2693-2703|
|Jacob, Andrew E; Turner, Christopher E; Amack, Jeffrey D (2016) Evolution and Expression of Paxillin Genes in Teleost Fish. PLoS One 11:e0165266|
|Goreczny, Gregory J; Wormer, Duncan B; Turner, Christopher E (2015) A Simplified System for Evaluating Cell Mechanosensing and Durotaxis In Vitro. J Vis Exp :e52949|
|Deakin, Nicholas O; Turner, Christopher E (2014) Paxillin inhibits HDAC6 to regulate microtubule acetylation, Golgi structure, and polarized migration. J Cell Biol 206:395-413|
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