Fig. 1

A (i) ERBB/HER family members and their cognate ligands (ii) Structural difference of various (I-VI) types of NRG1. Abbreviations: CD, cytoplastmic domain; CRD, Cysteine-rich domain; ECD, extracellular domain; EGF, epidermal growth factor; EGF-L; EGF-like repeat; HB-EGF, heparin-binding EGF-like growth factor; Ig, Ig-like C2-type domain; LIMK, LIM kinase; N-CoR, Nuclear receptor co-repressor; TA B2, TGF-Beta Activated Kinase 1 (MAP3K7) Binding Protein 2); TGF, transforming growth factor; TM, transmembrane; TMD, transmembrane domain; WT, wild type. B Examples of various fusions of NRG1. The structure of some representative variants of NRG1 fusions is shown. The EGF domain is preserved in all fusion proteins. C ERBB/HER family and potential downstream cascades. Figure represents possible sets for ERBB3/HER3 or ERBB4/HER4 dimerization with other ERBB/HER family members (HER1:HER4, HER1:HER3, HER2:HER4, HER4:HER4, HER3:HER4, and HER2:HER3) and their ligand(s) (e.g., NRG1, 2, 3, and 4) binding or their binding with EGF-like structure of NRG1 fusion-protein. Note that ERBB4/HER4 is also known as ALS19. NRG1 fusion-protein exerts a tumorigenic effect that requires HER2:HER3 heterodimerization-mediated activation, which can result in oncogenic signaling. The NRG1 fusion product is a transmembrane protein with an extracellular EGF-like domain that binds to ERBB3/HER3 in the cell membrane (see inside the box). NRG or NRG1-fusion-induced HER2:HER3 heterodimerization is depicted as the inset. The binding of ligands to receptors triggers dimerization and activation of the downstream signaling events responsible for tumorigenesis. Out of four family members, ERBB3/HER3 has six YXXM motifs responsible for the recruitment of p85, leading to activation of the PI3K-AKT-mTOR pathway. Other receptor dimerization also activates the RAS-RAF-MAPK pathway responsible for proliferation and survival. The NRG-HER signaling pathway also activates downstream JAK-STAT and PLCγ-PKC pathways, and both play a role in various oncogenic phenotypes. Examples of FDA-approved drugs are shown in the red color font, and examples of non-approved drugs are presented in blue font (inside the box). ERBB2/HER2 may also interact with ERBB3/HER3 and IGF1R to form heterotrimeric complex (HER2-HER3-IGF1R) [not shown in the figure] in trastuzumab-resistant breast cancer cells. D NRG1-mediated ERBB4/HER4 activation forward signaling (non-canonical). Non-canonical ERBB4/HER4 (also known as ALS19) forward signaling is shown. The ERBB4/HER4 intracellular domain is cleaved by γ-secretase (or others) (separated from the extracellular domain (ECD); the ERBB4/HER4 intracellular domain translocates to the nucleus to regulate gene expression. Also, NRG1-mediated HER4 activation (phosphorylation) promotes the association with an adaptor protein TA B2. TA B2 also recruits N-CoR and forms a signaling complex that, upon translocation to the nucleus, represses the transcription of certain genes required for the differentiation of neuronal precursor cells. E NRG1- mediated backward signaling. For NRG1-mediated backward signaling, the C-terminal fragment of NRG1 (CD: cytoplasmic domain) is cleaved from the Pro-NRG1 by the help of a protease; NRG1 CD may translocate to the nucleus to regulate gene transcription. The CD of Pro-NRG1 also interacts with LIM kinase (LIMK). LIMK (a non-receptor tyrosine kinase) has been shown to regulate cytoskeletal rearrangement/actin dynamics in many cell types including neuronal cells. In addition, ERBB4/HER4 (ALS19) or its diffusible extracellular domain can act as a ligand for pro-NRG1