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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Baker, Carl
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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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
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 135:1043-52
Hiroyasu, Sho; Jones, Jonathan C R (2014) A new component of the Fraser complex. J Invest Dermatol 134:1192-3
Hopkinson, Susan B; Hamill, Kevin J; Wu, Yvonne et al. (2014) Focal Contact and Hemidesmosomal Proteins in Keratinocyte Migration and Wound Repair. Adv Wound Care (New Rochelle) 3:247-263
Kligys, Kristina; Wu, Yvonne; Hamill, Kevin J et al. (2013) Laminin-332 and *3*1 integrin-supported migration of bronchial epithelial cells is modulated by fibronectin. Am J Respir Cell Mol Biol 49:731-40
Jeffe, Jill S; Seshadri, Sudarshan; Hamill, Kevin J et al. (2013) A role for anti-BP180 autoantibodies in chronic rhinosinusitis. Laryngoscope 123:2104-11
Hamill, Kevin J; Hopkinson, Susan B; Skalli, Omar et al. (2013) Actinin-4 in keratinocytes regulates motility via an effect on lamellipodia stability and matrix adhesions. FASEB J 27:546-56
Hiroyasu, Sho; Ozawa, Toshiyuki; Kobayashi, Hiromi et al. (2013) Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway. Am J Pathol 182:828-40
Hamill, Kevin J; Hopkinson, Susan B; Hoover, Paul et al. (2012) Fibronectin expression determines skin cell motile behavior. J Invest Dermatol 132:448-57
Kligys, Kristina R; Wu, Yvonne; Hopkinson, Susan B et al. (2012) α6β4 integrin, a master regulator of expression of integrins in human keratinocytes. J Biol Chem 287:17975-84

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