title: Granzyme B inhibits keratinocyte migration by disrupting epidermal growth factor receptor (EGFR)-mediated signaling.
abstract: Chronic non-healing wounds including diabetic, venous, and decubitus skin ulcers are currently lacking effective therapies. Non-healing diabetic ulcers can lead to amputations as progress into a highly chronic state before detection and existing treatments for these wounds often fail. Granzyme B (GzmB) is a serine protease that was, until recently, believed to function exclusively in cytotoxic lymphocyte-mediated apoptosis. However, during excessive or chronic inflammation, GzmB can accumulate in the extracellular milieu, retain its activity, and cleave a number of important extracellular proteins. Epidermal growth factor receptor (EGFR) is a transmembrane receptor involved in cellular processes such as proliferation and migration. EGFR signaling is integral to the wound healing process. The present study investigated the effects of GzmB on keratinocyte cell migration using HaCaT cell line. Using electric cell-substrate impedance sensing and scratch assays, the present study demonstrates that GzmB inhibits keratinocyte migration by interfering with the EGFR pathway. GzmB limited cell transition into a migratory morphology and was found to reduce ligand-induced EGFR phosphorylation. Inhibition of GzmB reversed the aforementioned effects. In summary, data from the present study suggest key role for GzmB in the pathogenesis of impaired wound healing through the impairment of EGFR signaling and cell migration.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Merkulova
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Leigh G
authors.initials: LG
authors.lastname: Parkinson
authors.forename: Sheetal A
authors.initials: SA
authors.lastname: Raithatha
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Kathryn
authors.initials: K
authors.lastname: Westendorf
authors.forename: Mehul
authors.initials: M
authors.lastname: Sharma
authors.forename: Robert Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D053804:Granzymes / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D066246:ErbB Receptors; D053804:Granzymes