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Published on: August 25, 2021
The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist
Kristy J Wilson1, Christopher P Mill, Richard M Gallo
1Purdue University College of Pharmacy and Purdue University Center for Cancer Research, West Lafayette, IN 47907-2064, USA.
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 NRG2β (neuregulin 2β) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2β/Q43L may be an ErbB4 antagonist. NRG2β/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2β/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2β. In addition, NRG2β stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2β stimulates greater Akt phosphorylation than does NRG2β/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 NRG2β and NRG2β/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2β/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2β/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2β/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, NRG2β/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.
Insights
A novel neuregulin 2β mutant (NRG2β/Q43L) acts as an ErbB4 antagonist, blocking proliferation and offering a new strategy for developing anti-ErbB therapeutics.
Area of Science:
- Molecular biology
- Cell signaling
- Cancer research
Background:
- ErbB4 receptor tyrosine kinase has dual roles in cancer, acting as both a tumor suppressor and oncogene.
- Existing ErbB4 agonists and antagonists have limitations, necessitating the development of novel antagonists.
- Understanding ErbB4 signaling pathways is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the potential of a neuregulin 2β mutant (NRG2β/Q43L) as an ErbB4 antagonist.
- To elucidate the mechanisms by which NRG2β/Q43L modulates ErbB4 signaling and cell proliferation.
- To explore the broader antagonistic activity of NRG2β/Q43L against other ErbB receptors.
Main Methods:
- Utilized NRG2β/Q43L mutant to study ErbB4 phosphorylation and cell proliferation.
- Assessed the role of phosphoinositide 3-kinase (PI3K) and Akt phosphorylation in NRG2β-mediated signaling.
- Investigated the involvement of epidermal growth factor receptor (EGFR) kinase activity in ErbB4 signaling.
- Examined the differential coupling of ErbB4 isoforms and mutants to YAP.
- Tested the antagonistic effects of NRG2β/Q43L on EGFR, ErbB2/ErbB3 signaling.
Main Results:
- NRG2β/Q43L competitively antagonizes ErbB4-mediated cell proliferation.
- NRG2β/Q43L induces less ErbB4 tyrosine phosphorylation compared to NRG2β.
- EGFR kinase activity, not ErbB4, is critical for coupling ErbB4 to proliferation.
- NRG2β/Q43L exhibits pan-ErbB antagonistic activity against EGFR and ErbB2/ErbB3.
- NRG2β/Q43L may differentially regulate ErbB4 coupling to YAP compared to NRG2β.
Conclusions:
- NRG2β/Q43L functions as a competitive ErbB4 antagonist, inhibiting proliferation.
- NRG2β/Q43L acts as a pan-ErbB antagonist, affecting multiple ErbB receptors.
- This study suggests a novel mechanism of ErbB receptor regulation involving distinct phosphorylation sites for agonists and antagonists.
- NRG2β/Q43L and similar antagonists provide a new paradigm for developing anti-ErbB therapeutics.
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