title: Eosinophil peroxidase activates cells by HER2 receptor engagement and β1-integrin clustering with downstream MAPK cell signaling.
abstract: Eosinophils account for 1-3% of peripheral blood leukocytes and accumulate at sites of allergic inflammation, where they play a pathogenic role. Studies have shown that treatment with mepolizumab (an anti-IL-5 monoclonal antibody) is beneficial to patients with severe eosinophilic asthma, however, the mechanism of precisely how eosinophils mediate these pathogenic effects is uncertain. Eosinophils contain several cationic granule proteins, including Eosinophil Peroxidase (EPO). The main significance of this work is the discovery of EPO as a novel ligand for the HER2 receptor. Following HER2 activation, EPO induces activation of FAK and subsequent activation of β1-integrin, via inside-out signaling. This complex results in downstream activation of ERK1/2 and a sustained up regulation of both MUC4 and the HER2 receptor. These data identify a receptor for one of the eosinophil granule proteins and demonstrate a potential explanation of the proliferative effects of eosinophils.
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Kerrie
authors: K
authors: Hennigan
authors: Biomedical Diagnostics Institute, Dublin City University, Dublin 9, Ireland.
authors: Paul J
authors: PJ
authors: Conroy
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Marie-Therese
authors: MT
authors: Walsh
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Mohamed
authors: M
authors: Amin
authors: Biomedical Diagnostics Institute, Dublin City University, Dublin 9, Ireland.
authors: Richard
authors: R
authors: O'Kennedy
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Patmapriya
authors: P
authors: Ramasamy
authors: Department of Dermatology, University of Utah, Salt Lake City, USA.
authors: Gerald J
authors: GJ
authors: Gleich
authors: Graduate Entry Medical School, University of Limerick, Ireland.
authors: Zeshan
authors: Z
authors: Siddiqui
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Senan
authors: S
authors: Glynn
authors: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Olive
authors: O
authors: McCabe
authors: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Catherine
authors: C
authors: Mooney
authors: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Brian J
authors: BJ
authors: Harvey
authors: Department of Medicine Respiratory Research Division, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. Electronic address: rcostello@rcsi.ie.
authors: Richard W
authors: RW
authors: Costello
authors: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
authors: Jean
authors: J
authors: McBryan
mesh_terms: D002460:Cell Line; D047209:Eosinophil Peroxidase / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D055264:Mucin-4 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047209:Eosinophil Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D051417:Focal Adhesion Kinase 1; D019012:Integrin beta1; D055264:Mucin-4; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C524658:MUC4 protein, human; C508053:ERBB2 protein, human; C496050:PTK2 protein, human
keywords: Eosinophil peroxidase; HER2; MUC4; β1-integrin