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Evaluation of Individual ErbB Receptor Contributions to Cellular Responses Initiated by GGF2
Author(s) -
Sarmiere Patrick,
Stricker Jason,
Cao Jing,
Cain Evan,
Srinivas Maya,
Vecchione Andrea,
Caggiano Tony,
Button Donald
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.934.7
Subject(s) - erbb , receptor tyrosine kinase , neuregulin , erbb3 , erbb4 , gene knockdown , microbiology and biotechnology , receptor , neuregulin 1 , biology , cancer research , tyrosine kinase , signal transduction , cell culture , biochemistry , genetics
Neuregulins control processes of both tissue development and homeostasis. Glial growth factor 2 (GGF2; Cimaglermin alfa [USAN]), a Type II isoform of the neuregulin 1 (Nrg1) gene, is a ligand selective for the ErbB3 and ErbB4 members of the EGFR‐family of receptor tyrosine kinases. GGF2 has been shown to be cardioprotective in both in vitro and in vivo injury models and is undergoing clinical testing for the treatment of chronic heart failure. The goal of this work was to define the roles of ErbB3 and ErbB4 receptors in GGF2‐mediated responses in a variety of cell types. Cell lines representing cardiac (HL1), liver (HepG2) and breast (MCF7) tissues were evaluated for ErbB receptor expression via qPCR and then specific receptor subtypes were targeted for knockdown of expression using siRNA. At times corresponding to maximal reduction of ErbB receptor protein levels, cells were stimulated with a range of GGF2 concentrations and evaluated for early Akt phosphorylation (pAkt) responses as well as longer term responses related to cell phenotype. Results from these studies indicate ErbB2, 3 and 4 all contribute to GGF2‐mediated pAkt formation in MCF7 and HL1 cells. However, in HepG2 cells, knockdown of ErbB3, but not ErbB2, attenuated GGF2‐dependent pAkt formation. Interestingly, reduction of ErbB4, but not ErbB3, reduced the cytoprotective effect of GGF2 in doxorubicin treated HL1 cells. Additional studies assessing other ErbB‐mediated signaling responses such as proliferation, maintenance of mitochondrial membrane potential and liver‐specific endpoints are being performed. Our results provide insight on the roles that ErbB receptors play in mediating GGF2 actions across a range of target cell types.