NRG1

The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

Neuregulin 1

Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Isoform 10 may play a role in motor and sensory neuron development. Binds to ERBB4 (PubMed:10867024, PubMed:7902537).
Binds to ERBB3 (PubMed:20682778).
Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling. Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:20682778).
Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (By similarity).

Activation of protein kinase B activityManual Assertion Based On ExperimentIMP:UniProtKB
Activation of transmembrane receptor protein tyrosine kinase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Animal organ developmentManual Assertion Based On ExperimentIBA:GO_Central
Cardiac conduction system developmentIEA:Ensembl
Cardiac muscle cell differentiationISS:BHF-UCL
Cardiac muscle cell myoblast differentiationManual Assertion Based On ExperimentIDA:BHF-UCL
Cell communicationManual Assertion Based On ExperimentTAS:BHF-UCL
Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cell morphogenesisIEA:Ensembl
Cell population proliferationIDA:BHF-UCL
Chemorepulsion involved in interneuron migration from the subpallium to the cortexIEA:Ensembl
Endocardial cell differentiationManual Assertion Based On ExperimentIDA:BHF-UCL
ERBB signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
ERBB3 signaling pathwayManual Assertion Based On ExperimentIDA:CAFA
ERBB4 signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
ERBB4-ERBB4 signaling pathwayManual Assertion Based On ExperimentIDA:MGI
Glial cell fate commitmentIEA:Ensembl
Intracellular signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Locomotory behaviorIEA:Ensembl
Mammary gland developmentManual Assertion Based On ExperimentTAS:BHF-UCL
MAPK cascadeIEA:Ensembl
Myelination in peripheral nervous systemIEA:Ensembl
Negative regulation of cardiac muscle cell apoptotic processIDA:BHF-UCL
Negative regulation of extrinsic apoptotic signaling pathway in absence of ligandIDA:BHF-UCL
Negative regulation of neuron migrationIEA:Ensembl
Negative regulation of protein catabolic processIEA:Ensembl
Negative regulation of secretionManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:MGI
Nervous system developmentManual Assertion Based On ExperimentIBA:GO_Central
Neural crest cell developmentManual Assertion Based On ExperimentTAS:BHF-UCL
Neuron fate commitmentIEA:Ensembl
Neurotransmitter receptor metabolic processIEA:Ensembl
Oligodendrocyte differentiationIEA:Ensembl
Positive regulation of calcineurin-NFAT signaling cascadeIEA:Ensembl
Positive regulation of cardiac muscle cell proliferationIDA:BHF-UCL
Positive regulation of cell adhesionIDA:BHF-UCL
Positive regulation of cell growthIDA:BHF-UCL
Positive regulation of cell population proliferationManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of ERK1 and ERK2 cascadeManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of gene expressionIEA:Ensembl
Positive regulation of peptidyl-tyrosine autophosphorylationIDA:UniProtKB
Positive regulation of protein kinase B signalingIEA:Ensembl
Positive regulation of protein-containing complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of Ras protein signal transductionIEA:Ensembl
Positive regulation of striated muscle cell differentiationISS:BHF-UCL
Postsynapse to nucleus signaling pathwayIEA:Ensembl
Protein-containing complex disassemblyIGI:MGI
Regulation of postsynaptic neurotransmitter receptor internalizationIDA:SynGO
Synapse assemblyIEA:Ensembl
Synaptic membrane adhesionIDA:SynGO
Transmembrane receptor protein tyrosine kinase signaling pathwayIDA:BHF-UCL
Ventricular cardiac muscle cell differentiationIDA:BHF-UCL
Ventricular trabecula myocardium morphogenesisManual Assertion Based On ExperimentIDA:BHF-UCL
Wound healingManual Assertion Based On ExperimentIDA:BHF-UCL

Pro-neuregulin-1, membrane-bound isoform
Cell membrane
Does not seem to be active.
Neuregulin-1
Secreted
Isoform 8
Nucleus
May be nuclear.
Isoform 9
Secreted
Has a signal peptide.
Isoform 10
Membrane
May possess an internal uncleaved signal sequence.

A chromosomal aberration involving NRG1 produces gamma-heregulin. Translocation t(8;11) with TENM4. The translocation fuses the 5'-end of TENM4 to NRG1 (isoform 8). The product of this translocation was first thought to be an alternatively spliced isoform. Gamma-heregulin is a soluble activating ligand for the ERBB2-ERBB3 receptor complex and acts as an autocrine growth factor in a specific breast cancer cell line (MDA-MB-175). Not detected in breast carcinoma samples, including ductal, lobular, medullary, and mucinous histological types, neither in other breast cancer cell lines.

Extracellular: 20-242
Helical: 243-265
Cytoplasmic: 266-640

Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form.
N- and O-glycosylated. Extensive glycosylation precedes the proteolytic cleavage (By similarity).