Specifically binds and is activated by neuregulins, NRG-2, NRG-3, heparin-binding EGF-like growth factor, betacellulin and NTAK. Interaction with these factors induces cell differentiation. Not activated by EGF, TGF-A, and amphiregulin. The C-terminal fragment (CTF) of isoform JMA-A CYT-2 (containing E4ICD2) can stimulate transcription in the presence of YAP1. ERBB4 intracellular domain is involved in the regulation of cell growth. Conflicting reports are likely due at least in part to the opposing effects of the isoform-specific and nuclear-translocated ERBB4 intracellular domains (E4ICD1 and E4ICD2). Overexpression studies in epithelium show growth inhibition using E4ICD1 and increased proliferation using E4ICD2. E4ICD2 has greater in vitro kinase activity than E4ICD1. The kinase activity is required for the nuclear translocation of E4ICD2 (By similarity).