NRG1

Official Full Name

neuregulin 1

Organism

Homo sapiens

GeneID

3084

Background

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]

Synonyms

GGF; HGL; HRG; NDF; ARIA; GGF2; HRG1; HRGA; SMDF; MST131; MSTP131; NRG1-IT2;

Protein Sequence

MSERKEGRGKGKGKKKERGSGKKPESAAGSQSPALPPRLKEMKSQESAAGSKLVLRCETSSEYSSLRFKWFKNGNELNRKNKPQNIKIQKKPGKSELRINKASLADSGEYMCKVISKLGNDSASANITIVESNEIITGMPASTEGAYVSSESPIRISVSTEGANTSSSTSTSTTGTSHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCTENVPMKVQNQEKAEELYQKRVLTITGICIALLVVGIMCVVAYCKTKKQRKKLHDRLRQSLRSERNNMMNIANGPHHPNPPPENVQLVNQYVSKNVISSEHIVEREAETSFSTSHYTSTAHHSTTVTQTPSHSWSNGHTESILSESHSVIVMSSVENSRHSSPTGGPRGRLNGTGGPRECNSFLRHARETPDSYRDSPHSERYVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVSMPSMAVSPFMEEERPLLLVTPPRLREKKFDHHPQQFSSFHHNPAHDSNSLPASPLRIVEDEEYETTQEYEPAQEPVKKLANSRRAKRTKPNGHIANRLEVDSNTSSQSSNSESETEDERVGEDTPFLGIQNPLAASLEATPAFRLADSRTNPAGRFSTQEEIQARLSSVIANQDPIAV

Open

Disease

Heart failure

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

Neuroregulatory proteins (NRGs) are a family of growth factors with multiple effects and play an important role in many neurological disorders (including multiple sclerosis, brain trauma, spinal cord injury, peripheral neuropathy, and schizophrenia). There are four kinds of NRRG genes in mammals, which are coded as NRG1, NRG2, NRG3 and NRG4, respectively. NRG originated from the isolation and extraction of nerve tissue, because it can promote the proliferation of Schwann cells in the nervous system, also known as glial growth factor. Among them, the research of NRG1 is the most extensive. The NRG1 gene is located on chromosome 8 of humans and mice and can encode 21 kinds of exons. By selective splicing and different promoters, at least 31 subtypes including secreted and cross-model can be generated. NRG1 has a wide range of roles in the development of the nervous system, heart, and breast. It can regulate synaptic plasticity, stimulate proliferation and survival, and regulate the activity of many different cell types.

NRG1 Figure 1. Schematic of BACE1-dependent NRG1/ErbB4 signaling pathway involving in the pathogenies of schizophrenia. (Zhengrong, Z., et al. 2017)

NRG1 and Its Receptor ErbB

NRG1 subtypes all contain an EGF-like signaling domain, which is indispensable for regulating biological activity. NRG1 needs to bind to the dimerization receptor to transmit signals. First, the EGF-like domain is bound to the tyrosine kinase receptor ErbB3 or ErbB4. ErbB3 or ErbB4 then forms a heterodimer with ErbB2. ErbB2 lacks a ligand-binding domain, so it acts as a co-receptor in signal transduction, while ErbB3 lacks an activated tyrosine kinase domain, and must bind to ErbB2 for signal transduction. In the peripheral nervous system, NRG1/ErbB is a key regulator of the axon-Schwann cell connection and can regulate Schwann cell development. NRG1 can induce neural crest cells to differentiate, proliferate, and migrate to Schwann cells, and promote the survival of embryonic Schwann cell precursor cells and immature Schwann cells, which is necessary for the normal formation and sensory function of myelin sheath. In the central nervous system, NRG1 promotes the proliferation of microglia and participates in the formation and development of neuropathic pain by binding to the ErbB2 receptor on the microglia membrane of the dorsal horn of the spinal cord.

NRG1 and Neuropathic Pain

The study found that only intrathecal injection of NRG1-β1 protein in rats can significantly reduce the tactile withdrawal threshold of the hind paws of rats, resulting in transient touch-induced pain. The study found that excluding schizophrenia-related gene NRG1 reduced the sensitivity to heat pain in mice, suggesting that the NRG1 gene may be closely related to pain and heat perception abnormalities in patients with schizophrenia. In a mixed bone cancer pain model of neuropathic pain and inflammatory pain, it was found that 3 weeks after injection of tumor cells, time-dependent levels of NRG1, ErbB2, and phosphorylated ErbB2 increased, and exogenous NRG1 was administered intrathecally. Up-regulation of ErbB2 and phosphorylated ErbB2 messenger RNA and protein levels produce thermal hyperalgesia and mechanical hyperalgesia, while ErbB2 signaling inhibitors greatly reduce thermal hyperalgesia and mechanical hyperalgesia in cancerous bone pain. In a phase II clinical trial, it was found that the ErbB2 inhibitor lapatinib used for breast cancer treatment can improve the symptoms and reduce pain at the same time. Further research found that in the model of facial nerve injury, ErbB3 levels and mechanical touch sensation increased synchronously with time, and lapatinib could significantly reduce mechanical touch evoked pain in a dose-dependent manner.

References:

Zhengrong, Z. , Jing, H. , Yong, S. , & Rena, L. . (2017). Bace1-dependent neuregulin-1 signaling: an implication for schizophrenia. Frontiers in Molecular Neuroscience, 10, 302-.
Soury, M. E. , & Gambarotta, G. . (2019). Soluble neuregulin-1 (nrg1): a factor promoting peripheral nerve regeneration by affecting schwann cell activity immediately after injury. Neural Regeneration Research, 14(8), 1374.
Jonna, S. , Feldman, R. A. , Swensen, J. , Gatalica, Z. , Korn, W. M. , & Borghaei, H. , et al. (2019). Detection of nrg1 gene fusions in solid tumors. Clinical Cancer Research.

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