Target Information
| Target General Information | Top | |||||
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| Target ID |
T65198
(Former ID: TTDR00668)
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| Target Name |
Pro-neuregulin-1 (Pro-NRG1)
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| Synonyms |
SMDF (20-241); Pro-neuregulin-1, membrane-bound isoform (20-241); NDF (20-241); Heregulin (20-241); HRGA (20-241); HGL (20-241); GGF (20-241)
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| Gene Name |
NRG1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| Function |
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. Binds to ERBB3. 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. Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons. Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors.
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| UniProt ID | ||||||
| Sequence |
MSERKEGRGKGKGKKKERGSGKKPESAAGSQSPALPPRLKEMKSQESAAGSKLVLRCETS
SEYSSLRFKWFKNGNELNRKNKPQNIKIQKKPGKSELRINKASLADSGEYMCKVISKLGN DSASANITIVESNEIITGMPASTEGAYVSSESPIRISVSTEGANTSSSTSTSTTGTSHLV KCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCTENVPMKVQNQEKAEELYQ KRVLTITGICIALLVVGIMCVVAYCKTKKQRKKLHDRLRQSLRSERNNMMNIANGPHHPN PPPENVQLVNQYVSKNVISSEHIVEREAETSFSTSHYTSTAHHSTTVTQTPSHSWSNGHT ESILSESHSVIVMSSVENSRHSSPTGGPRGRLNGTGGPRECNSFLRHARETPDSYRDSPH SERYVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVSMPSMAVSPFMEEERPLLL VTPPRLREKKFDHHPQQFSSFHHNPAHDSNSLPASPLRIVEDEEYETTQEYEPAQEPVKK LANSRRAKRTKPNGHIANRLEVDSNTSSQSSNSESETEDERVGEDTPFLGIQNPLAASLE ATPAFRLADSRTNPAGRFSTQEEIQARLSSVIANQDPIAV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T68OE2 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | Neucardin | Drug Info | Phase 3 | Heart failure | [2] | |
| 2 | GGF | Drug Info | Phase 1b | Congestive heart failure | [3] | |
| 3 | GGF-2 | Drug Info | Phase 1 | Heart failure | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Neucardin | Drug Info | [1] | |||
| 2 | GGF | Drug Info | [5] | |||
| 3 | GGF-2 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| ErbB signaling pathway | hsa04012 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 5.03E-05 |
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| Closeness centrality | 2.26E-01 | Radiality | 1.40E+01 | Clustering coefficient | 6.19E-01 |
| Neighborhood connectivity | 5.37E+01 | Topological coefficient | 2.20E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | ErbB signaling pathway | |||||
| Reactome | [+] 9 Reactome Pathways | + | ||||
| 1 | SHC1 events in ERBB2 signaling | |||||
| 2 | PI3K events in ERBB4 signaling | |||||
| 3 | SHC1 events in ERBB4 signaling | |||||
| 4 | Nuclear signaling by ERBB4 | |||||
| 5 | PIP3 activates AKT signaling | |||||
| 6 | GRB2 events in ERBB2 signaling | |||||
| 7 | PI3K events in ERBB2 signaling | |||||
| 8 | Constitutive Signaling by Aberrant PI3K in Cancer | |||||
| 9 | RAF/MAP kinase cascade | |||||
| WikiPathways | [+] 9 WikiPathways | + | ||||
| 1 | ErbB Signaling Pathway | |||||
| 2 | NRF2 pathway | |||||
| 3 | Nuclear Receptors Meta-Pathway | |||||
| 4 | Apoptosis-related network due to altered Notch3 in ovarian cancer | |||||
| 5 | Cardiac Hypertrophic Response | |||||
| 6 | Signaling by ERBB4 | |||||
| 7 | Signaling by ERBB2 | |||||
| 8 | Cardiac Progenitor Differentiation | |||||
| 9 | MicroRNAs in cardiomyocyte hypertrophy | |||||
| References | Top | |||||
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| REF 1 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 2 | ClinicalTrials.gov (NCT01214096) Clinical Trial to Evaluate the Efficacy and Safety of Recombinant Human Neuregulin-1 for Subcutaneous Administration in Patients With Chronic Systolic Heart Failure. U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of Acorda Therapeutics. | |||||
| REF 4 | ClinicalTrials.gov (NCT01258387) Single Ascending Doses of GGF2 in Patients With Left Ventricular Dysfunction and Symptomatic Heart Failure. U.S. National Institutes of Health. | |||||
| REF 5 | Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination. J Cell Biol. 2001 Mar 19;152(6):1289-99. | |||||
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