Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension

Olga Rafikova, Ruslan Rafikov, Archana Kangath, Ning Qu, Saurabh Aggarwal, Shruti Sharma, Julin Desai, Taylor Fields, Britta Ludewig, Jason Yuan, Danny Jonigk, Stephen M. Black

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The development of pulmonary hypertension (PH) involves the uncontrolled proliferation of pulmonary smooth muscle cells via increased growth factor receptor signaling. However, the role of epidermal growth factor receptor (EGFR) signaling is controversial, as humans with advanced PH exhibit no changes in EGFR protein levels and purpose of the present study was to determine whether there are post-translational mechanisms that enhance EGFR signaling in PH. The EGFR inhibitor, gefinitib, significantly attenuated EGFR signaling and prevented the development of PH in monocrotaline (MCT)-exposed rats, confirming the contribution of EGFR activation in MCT induced PH. There was an early MCT-mediated increase in hydrogen peroxide, which correlated with the binding of the active metabolite of MCT, monocrotaline pyrrole, to catalase Cys377, disrupting its multimeric structure. This early oxidative stress was responsible for the oxidation of EGFR and the formation of sodium dodecyl sulfate (SDS) stable EGFR dimers through dityrosine cross-linking. These cross-linked dimers exhibited increased EGFR autophosphorylation and signaling. The activation of EGFR signaling did not correlate with pp60src dependent Y845 phosphorylation or EGFR ligand expression. Importantly, the analysis of patients with advanced PH revealed the same enhancement of EGFR autophosphorylation and covalent dimer formation in pulmonary arteries, while total EGFR protein levels were unchanged. As in the MCT exposed rat model, the activation of EGFR in human samples was independent of pp60src phosphorylation site and ligand expression. This study provides a novel molecular mechanism of oxidative stress stimulated covalent EGFR dimerization via tyrosine dimerization that contributes into development of PH.

Original languageEnglish (US)
Pages (from-to)96-111
Number of pages16
JournalFree Radical Biology and Medicine
Volume95
DOIs
StatePublished - Jun 1 2016

Keywords

  • Catalase
  • EGFR
  • Oxidative stress
  • Proliferation
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Rafikova, O., Rafikov, R., Kangath, A., Qu, N., Aggarwal, S., Sharma, S., Desai, J., Fields, T., Ludewig, B., Yuan, J., Jonigk, D., & Black, S. M. (2016). Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension. Free Radical Biology and Medicine, 95, 96-111. https://doi.org/10.1016/j.freeradbiomed.2016.02.029