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NRG2α, unlike NRG2β, fails to stimulate ErbB4 coupling to interleukin-3 (IL3) independence in BaF3 lymphoid z vad fmk [10] and [11]. Moreover, the NRG2α K45F mutant fails to stimulate ErbB4 coupling and the analogous NRG2β F45K mutant does stimulate ErbB4 coupling. Thus, it appears that NRG2β is a full agonist for ErbB4 whereas NRG2α is a partial agonist for ErbB4. Moreover, the failure of NRG2α to stimulate ErbB4 coupling to IL3 independence is not due to inadequate affinity for ErbB4 but instead reflects a difference in the intrinsic activity of NRG2α and NRG2β.
Here we investigate this difference. We demonstrate that the NRG2β Q43L mutant fails to stimulate ErbB4 coupling to IL3 independence, but is still a potent stimulus of ErbB4 tyrosine phosphorylation. Likewise, we demonstrate that the analogous NRG2α L43Q/K45F mutant stimulates ErbB4 coupling to IL3 independence. Thus, our data indicate that Gln43 of NRG2β is necessary and sufficient for NRG2 stimulation of ErbB4 coupling and regulates the intrinsic activity (efficacy) of NRG2 isoforms.