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Granzyme B inhibits keratinocyte migration by disrupting epidermal growth factor receptor (EGFR)-mediated signaling.

University of British Columbia

Chronic skin ulceration is a common complication and cause of morbidity in the elderly, diabetic, obese and/or immobile populations. Effective therapies that adequately promote efficient closure and remodelling of chronic wounds are lacking. Inflammation and excessive protease accumulation and activity are thought to play key roles in the impairment of normal wound healing. Granzyme B (GzmB) is a serine protease that was, until recently, believed to function exclusively in cytotoxic lymphocyte-mediated apoptosis. However, during dysregulated and/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. I hypothesized that GzmB impairs EGF-induced keratinocyte migration by impairing EGFR signaling. The present study investigated the effects of GzmB on keratinocyte cell migration. Using Electric Cell Substrate Impedance Sensing (ECIS) and other in vitro wound healing 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 HaCaT cells. In summary, data from the present study suggests a key role for GzmB in the pathogenesis of impaired wound healing through the reduction of EGFR signaling and cell migration.

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2016-05-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58050

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/