Recombinant Human Pro-neuregulin-1, membrane-bound isoform (NRG1)，Partial (Active)

Function

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)

Subcellular Location

Membrane (Single-pass type I membrane protein)

Disease Association

[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]

Tissue Specificity

Type I isoforms are the predominant forms expressed in the endocardium. Isoform alpha is expressed in breast, ovary, testis, prostate, heart, skeletal muscle, lung, placenta liver, kidney, salivary gland, small intestine and brain, but not in uterus, stomach, pancreas, and spleen. Isoform 3 is the predominant form in mesenchymal cells and in non-neuronal organs, whereas isoform 6 is the major neuronal form. Isoform 8 is expressed in spinal cord and brain. Isoform 9 is the major form in skeletal muscle cells; in the nervous system it is expressed in spinal cord and brain. Also detected in adult heart, placenta, lung, liver, kidney, and pancreas. Isoform 10 is expressed in nervous system: spinal cord motor neurons, dorsal root ganglion neurons, and brain. Predominant isoform expressed in sensory and motor neurons. Not detected in adult heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Not expressed in fetal lung, liver and kidney. Type IV isoforms are brain-specific

Subunit

The cytoplasmic domain interacts with the LIM domain region of LIMK1 (By similarity). Forms a ternary complex with ERBB3 and ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:20682778). Interacts with NRDC and BACE1 (By similarity)

• Holmes W.E. et al. Identification of heregulin, a specific activator of p185erbB2. — Science (1992)
• Wen D. et al. Structural and functional aspects of the multiplicity of Neu differentiation factors. — Mol. Cell. Biol. (1994)
• Marchionni M.A. et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. — Nature (1993)
• Ho W.-H. et al. Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons. — J. Biol. Chem. (1995)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Nusbaum C. et al. DNA sequence and analysis of human chromosome 8. — Nature (2006)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• Schaefer G. et al. Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. — Oncogene (1997)