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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054184-24
Application #
8731055
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1988-04-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
24
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Pullman
State
WA
Country
United States
Zip Code
99164
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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
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
Boykins, Lou G; Jones, Jonathan C R; EstraƱo, Carlos E et al. (2016) Pre-embedding Double-Label Immunoelectron Microscopy of Chemically Fixed Tissue Culture Cells. Methods Mol Biol 1474:217-32
Shelden, Eric A; Colburn, Zachary T; Jones, Jonathan C R (2016) Focusing super resolution on the cytoskeleton. F1000Res 5:
Jones, Jonathan C R (2016) Pre- and Post-embedding Immunogold Labeling of Tissue Sections. Methods Mol Biol 1474:291-307
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
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
Hamill, Kevin J; Hiroyasu, Sho; Colburn, Zachary T et al. (2015) Alpha actinin-1 regulates cell-matrix adhesion organization in keratinocytes: consequences for skin cell motility. J Invest Dermatol 135:1043-1052

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