The Q43L mutant of neuregulin 2? is a pan-ErbB receptor antagonist.

ABSTRACT: The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2? (neuregulin 2?) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2?/Q43L may be an ErbB4 antagonist. NRG2?/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2?/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2?. In addition, NRG2? stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2? stimulates greater Akt phosphorylation than does NRG2?/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2? and NRG2?/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2?/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2?/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2?/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2?/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.

SUBMITTER: Wilson KJ 

PROVIDER: S-EPMC3960720 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature