In normal skin integrin 1624 resides at the hemidesmosome and stabilizes cell interaction with laminin-332 in the extracellular matrix. However, there is also evidence that 1624 integrin is involved in cell migration during wound healing. In this renewal, we propose four aims, focused on providing new insight into the molecular mechanisms via which 1624 integrin and its associated proteins regulate keratinocyte motility and wound healing.
In aim 1, we present preliminary data suggesting that the 3'UTR of 16 integrin mRNA is an important modulator of the expression of 24 integrin protein. We will test the hypothesis that it encodes a """"""""zipcode"""""""" and facilitates the co-localization and co- translation of 16 and 24 integrin mRNA.
Aim 2 is premised on preliminary data indicating that the Bullous Pemphigoid Antigen 2 (BPAG2) regulates keratinocyte migration/wound healing by mediating BPAG1e interaction with 1624 integrin. Thus, in aim 3, we will define precisely the molecular mechanisms underlying this function. We will also assess whether BPAG2 is involved in linking 1624 integrin to the actin cytoskeleton and, hence, the motility machinery of the keratinocyte. During the last grant period, we presented evidence that the Bullous Pemphigoid Antigen 1e (BPAG1e, BP230) is required for 1624 integrin-induced signal transduction by mediating 1624 integrin interaction with Rac and Rac activation, an essential requirement for directed skin cell migration in wound healing. We build on this finding in aim 3 by determining precisely how BPAG1e modulates 1624 integrin signaling and function in vitro and in vivo. The results from our three aims should provide mechanistic insight into how 1624 integrin heterodimers and their associated proteins contribute to skin cell motility and the wound healing process.
The coverage of wounds of the skin requires movement of cells over the wound surface. Understanding the molecular mechanisms that regulate this movement is essential for the development of new therapeutic strategies for the treatment of chronic wounds. Our goal is to dissect how a particular cell surface complex in the cells of the skin regulates cell motility and wound closure.
| Colburn, Zachary T; Jones, Jonathan C R (2018) Complexes of ?6?4 integrin and vimentin act as signaling hubs to regulate epithelial cell migration. J Cell Sci 131: |
| Colburn, Zachary T; Jones, Jonathan C R (2017) ?6?4 Integrin Regulates the Collective Migration of Epithelial Cells. Am J Respir Cell Mol Biol 56:443-452 |
| Jones, Jonathan C R; Kam, Chen Yuan; Harmon, Robert M et al. (2017) Intermediate Filaments and the Plasma Membrane. Cold Spring Harb Perspect Biol 9: |
| Hiroyasu, Sho; Stimac, Gregory P; Hopkinson, Susan B et al. (2017) Loss of ?-PIX inhibits focal adhesion disassembly and promotes keratinocyte motility via myosin light chain activation. J Cell Sci 130:2329-2343 |
| Moazedi-Fuerst, Florentine C; Gruber, Gerald; Stradner, Martin H et al. (2016) Effect of Laminin-A4 inhibition on cluster formation of human osteoarthritic chondrocytes. J Orthop Res 34:419-26 |
| Hiroyasu, Sho; Colburn, Zachary T; Jones, Jonathan C R (2016) A hemidesmosomal protein regulates actin dynamics and traction forces in motile keratinocytes. FASEB J 30:2298-310 |
| Boykins, Lou G; Jones, Jonathan C R; Estraño, Carlos E et al. (2016) Pre-embedding Double-Label Immunoelectron Microscopy of Chemically Fixed Tissue Culture Cells. Methods Mol Biol 1474:217-32 |
| Jones, Jonathan C R (2016) Pre- and Post-embedding Immunogold Labeling of Tissue Sections. Methods Mol Biol 1474:291-307 |
| Shelden, Eric A; Colburn, Zachary T; Jones, Jonathan C R (2016) Focusing super resolution on the cytoskeleton. F1000Res 5: |
| Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L et al. (2015) Lung-specific loss of ?3 laminin worsens bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 52:503-12 |
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