ERBB3

Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene.

ERBB3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1M6B, 2L9U, 3KEX, 3LMG, 3P11, 4LEO, 4OTW, 4P59, 4RIW, 4RIX, 4RIY, 5CUS
Identifiers
Aliases	ERBB3, ErbB-3, HER3, LCCS2, MDA-BF-1, c-erbB-3, c-erbB3, erbB3-S, p180-ErbB3, p45-sErbB3, p85-sErbB3, erb-b2 receptor tyrosine kinase 3, FERLK
External IDs	OMIM: 190151 MGI: 95411 HomoloGene: 20457 GeneCards: ERBB3
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q13.2 Start 56,076,799 bp[1] End 56,103,505 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 D3|10 77.1 cM Start 128,567,523 bp[2] End 128,589,652 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • protein tyrosine kinase activator activity • growth factor binding • protein homodimerization activity • kinase activity • GO:0001948 protein binding • identical protein binding • protein heterodimerization activity • ATP binding • transmembrane signaling receptor activity • neuregulin binding • phosphatidylinositol-4,5-bisphosphate 3-kinase activity • Ras guanyl-nucleotide exchange factor activity • protein tyrosine kinase activity • ubiquitin protein ligase binding • receptor tyrosine kinase • neuregulin receptor activity • transmembrane receptor protein tyrosine kinase activity Cellular component • integral component of membrane • lateral plasma membrane • membrane • cell membrane • integral component of plasma membrane • extracellular region • basolateral plasma membrane • apical plasma membrane • intracellular • receptor complex • extracellular • cytoplasm • basal plasma membrane Biological process • neuron apoptotic process • negative regulation of cell adhesion • phosphorylation • endocardial cushion development • positive regulation of protein tyrosine kinase activity • wound healing • MAPK cascade • positive regulation of calcineurin-NFAT signaling cascade • heart development • protein phosphorylation • negative regulation of secretion • regulation of cell proliferation • extrinsic apoptotic signaling pathway in absence of ligand • phosphatidylinositol 3-kinase signaling • positive regulation of phosphatidylinositol 3-kinase signaling • negative regulation of signal transduction • signal transduction • cranial nerve development • negative regulation of neuron apoptotic process • Schwann cell differentiation • phosphatidylinositol phosphorylation • regulation of cell motility • peripheral nervous system development • transmembrane receptor protein tyrosine kinase signaling pathway • ERBB2 signaling pathway • peptidyl-tyrosine phosphorylation • positive regulation of cardiac muscle tissue development • positive regulation of gene expression • positive regulation of protein kinase B signaling • cell differentiation • negative regulation of apoptotic process • positive regulation of ERK1 and ERK2 cascade • nervous system development • positive regulation of cell proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2065	13867
Ensembl	ENSG00000065361	ENSMUSG00000018166
UniProt	P21860	Q61526
RefSeq (mRNA)	NM_001982 NM_001005915	NM_010153
RefSeq (protein)	NP_001005915 NP_001973	NP_034283
Location (UCSC)	Chr 12: 56.08 – 56.1 Mb	Chr 10: 128.57 – 128.59 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. The kinase-impaired ErbB3 is known to form active heterodimers with other members of the ErbB family, most notably the ligand binding-impaired ErbB2.

Gene and expression

The human ERBB3 gene is located on the long arm of chromosome 12 (12q13). It is encoded by 23,651 base pairs and translates into 1342 amino acids.[5]

During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium.[6] ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system.[7]

Structure

ErbB3, like the other members of the ErbB receptor tyrosine kinase family, consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains four subdomains (I-IV). Subdomains I and III are leucine-rich and are primarily involved in ligand binding. Subdomains II and IV are cysteine-rich and most likely contribute to protein conformation and stability through the formation of disulfide bonds. Subdomain II also contains the dimerization loop required for dimer formation.[8] The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain.[9]

Unliganded receptor adopts a conformation that inhibits dimerization. Binding of neuregulin to the ligand binding subdomains (I and III) induces a conformational change in ErbB3 that causes the protrusion of the dimerization loop in subdomain II, activating the protein for dimerization.[9]

Function

ErbB3 has been shown to bind the ligands heregulin[10] and NRG-2.[11] Ligand binding causes a change in conformation that allows for dimerization, phosphorylation, and activation of signal transduction. ErbB3 can heterodimerize with any of the other three ErbB family members. The theoretical ErbB3 homodimer would be non-functional because the kinase-impaired protein requires transphosphorylation by its binding partner to be active.[9]

Unlike the other ErbB receptor tyrosine kinase family members which are activated through autophosphorylation upon ligand binding, ErbB3 was found to be kinase impaired, having only 1/1000 the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins.[12] Therefore, ErbB3 must act as an allosteric activator.

Interaction with ErbB2

The ErbB2-ErbB3 dimer is considered the most active of the possible ErbB dimers, in part because ErbB2 is the preferred dimerization partner of all the ErbB family members, and ErbB3 is the preferred partner of ErbB2.[13] This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ.[14] There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands.[15][16]

Activation of the PI3K/Akt pathway

The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K.[17] ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K,[14] a function not found in either EGFR or ErbB2.

Role in cancer

While no evidence has been found that ErbB3 overexpression, constitutive activation, or mutation alone is oncogenic,[18] the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis.[19][20]

ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to:

• HER2 inhibitors in HER2+ breast cancers[21]
• anti-estrogen therapy in ER⁺ breast cancers[22][23]
• EGFR inhibitors in lung and head and neck cancers[24][25]
• hormones in prostate cancers[26]
• IGF1R inhibitors in hepatomas[27]
• BRAF inhibitors in melanoma[28]

ErbB2 overexpression may promote the formation of active heterodimers with ErbB3 and other ErbB family members without the need for ligand binding, resulting in weak but constitutive signaling activity.[14]

Role in normal development

ERBB3 is expressed in the mesenchyme of the endocardial cushion, which will later develop into the valves of the heart. ErbB3 null mouse embryos show severely underdeveloped atrioventricular valves, leading to death at embryonic day 13.5. Although this function of ErbB3 depends on neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue.[29]

ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system[30] and neural crest derivatives such as Schwann cells.[31]

See also

• Epidermal growth factor receptor family
• Epidermal growth factor receptor
• Receptor tyrosine-kinases

References

1. GRCh38: Ensembl release 89: ENSG00000065361 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018166 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "ERBB3 Gene – GeneCards | ERBB3 Protein".
6. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science. 230 (4730): 1132–9. doi:10.1126/science.2999974. PMID 2999974.
7. Prigent SA, Lemoine NR, Hughes CM, Plowman GD, Selden C, Gullick WJ (1992). "Expression of the c-erbB-3 protein in normal human adult and fetal tissues". Oncogene. 7 (7): 1273–8. PMID 1377811.
8. Cho HS, Leahy DJ (2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–3. doi:10.1126/science.1074611. PMID 12154198. S2CID 23069349.
9. Roskoski R (2014). "The ErbB/HER family of protein-tyrosine kinases and cancer". Pharmacol. Res. 79: 34–74. doi:10.1016/j.phrs.2013.11.002. PMID 24269963.
10. Carraway KL, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA (1994). "The erbB3 gene product is a receptor for heregulin". J. Biol. Chem. 269 (19): 14303–6. doi:10.1016/S0021-9258(17)36789-3. PMID 8188716.
11. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C (1997). "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases". Nature. 387 (6632): 512–6. doi:10.1038/387512a0. PMID 9168115. S2CID 4310136.
12. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA (2010). "ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation". Proc. Natl. Acad. Sci. U.S.A. 107 (17): 7692–7. doi:10.1073/pnas.1002753107. PMC 2867849. PMID 20351256.
13. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y (1996). "A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor". Mol. Cell. Biol. 16 (10): 5276–87. doi:10.1128/MCB.16.10.5276. PMC 231527. PMID 8816440.
14. Citri A, Skaria KB, Yarden Y (2003). "The deaf and the dumb: the biology of ErbB-2 and ErbB-3". Exp. Cell Res. 284 (1): 54–65. doi:10.1016/s0014-4827(02)00101-5. PMID 12648465.
15. Pinkas-Kramarski R, Lenferink AE, Bacus SS, Lyass L, van de Poll ML, Klapper LN, Tzahar E, Sela M, van Zoelen EJ, Yarden Y (1998). "The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin". Oncogene. 16 (10): 1249–58. doi:10.1038/sj.onc.1201642. PMID 9546426. S2CID 25652800.
16. Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M, Fedi P, Tang C, Lippman M, Pierce JH (1997). "Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors". EMBO J. 16 (18): 5608–17. doi:10.1093/emboj/16.18.5608. PMC 1170193. PMID 9312020.
17. Prigent SA, Gullick WJ (1994). "Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera". EMBO J. 13 (12): 2831–41. doi:10.1002/j.1460-2075.1994.tb06577.x. PMC 395164. PMID 8026468.
18. Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A, Yoshinaga SK (1996). "Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2". J. Biol. Chem. 271 (7): 3884–90. doi:10.1074/jbc.271.7.3884. PMID 8632008. S2CID 7190224.
19. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE (2003). "The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8933–8. doi:10.1073/pnas.1537685100. PMC 166416. PMID 12853564.
20. Wang S, Huang X, Lee CK, Liu B (2010). "Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin". Oncogene. 29 (29): 4225–36. doi:10.1038/onc.2010.180. PMID 20498641. S2CID 22169790.
21. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007). "Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3". Nature. 445 (7126): 437–41. doi:10.1038/nature05474. PMC 3025857. PMID 17206155.
22. Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC (2007). "Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer". Int. J. Oncol. 30 (2): 509–20. doi:10.3892/ijo.30.2.509 (inactive 2021-01-14). PMID 17203234.CS1 maint: DOI inactive as of January 2021 (link)
23. Miller TW, Pérez-Torres M, Narasanna A, Guix M, Stål O, Pérez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, Lindsley CW, Arteaga CL (2009). "Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer". Cancer Res. 69 (10): 4192–201. doi:10.1158/0008-5472.CAN-09-0042. PMC 2724871. PMID 19435893.
24. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA (2007). "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling". Science. 316 (5827): 1039–43. doi:10.1126/science.1141478. PMID 17463250. S2CID 23254145.
25. Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P, Kulmala J, Pulkkinen J, Grenman R, Elenius K (2006). "Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells". Clin. Cancer Res. 12 (13): 4103–11. doi:10.1158/1078-0432.CCR-05-2404. PMID 16818711. S2CID 5571305.
26. Zhang Y, Linn D, Liu Z, Melamed J, Tavora F, Young CY, Burger AM, Hamburger AW (2008). "EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance". Mol. Cancer Ther. 7 (10): 3176–86. doi:10.1158/1535-7163.MCT-08-0526. PMC 2629587. PMID 18852121.
27. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël MJ, Fartoux L, Venot C, Bladt F, Housset C, Rosmorduc O (2009). "Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma". Clin. Cancer Res. 15 (17): 5445–56. doi:10.1158/1078-0432.CCR-08-2980. PMID 19706799. S2CID 207699374.
28. Kugel, C. H.; Hartsough, E. J.; Davies, M. A.; Setiady, Y. Y.; Aplin, A. E. (July 17, 2014). "Function-Blocking ERBB3 Antibody Inhibits the Adaptive Response to RAF Inhibitor". The Journal of Cancer Research. 74 (15): 4122–4132. doi:10.1158/0008-5472.CAN-14-0464. PMC 4120074. PMID 25035390.
29. Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997). "Severe neuropathies in mice with targeted mutations in the ErbB3 receptor". Nature. 389 (6652): 725–30. doi:10.1038/39593. PMID 9338783. S2CID 28741273.
30. Britsch, S; Li, L; Kirchhoff, S; Theuring, F; Brinkmann, V; Birchmeier, C; Riethmacher, D (1998). "The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system". Genes & Development. 12 (12): 1825–36. doi:10.1101/gad.12.12.1825. PMC 316903. PMID 9637684.
31. Davies AM (1998). "Neuronal survival: early dependence on Schwann cells". Curr. Biol. 8 (1): R15–8. doi:10.1016/s0960-9822(98)70009-0. PMID 9427620. S2CID 2745201.

Further reading

• Corfas G, Roy K, Buxbaum JD (2004). "Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia". Nat. Neurosci. 7 (6): 575–80. doi:10.1038/nn1258. PMID 15162166. S2CID 10692780.
• Plowman GD, Whitney GS, Neubauer MG, et al. (1990). "Molecular cloning and expression of an additional epidermal growth factor receptor-related gene". Proc. Natl. Acad. Sci. U.S.A. 87 (13): 4905–9. doi:10.1073/pnas.87.13.4905. PMC 54229. PMID 2164210.
• Kraus MH, Issing W, Miki T, et al. (1990). "Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9193–7. doi:10.1073/pnas.86.23.9193. PMC 298460. PMID 2687875.
• Alimandi M, Romano A, Curia MC, et al. (1995). "Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas". Oncogene. 10 (9): 1813–21. PMID 7538656.
• Wallasch C, Weiss FU, Niederfellner G, et al. (1995). "Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3". EMBO J. 14 (17): 4267–75. doi:10.1002/j.1460-2075.1995.tb00101.x. PMC 394510. PMID 7556068.
• Horan T, Wen J, Arakawa T, et al. (1995). "Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3". J. Biol. Chem. 270 (41): 24604–8. doi:10.1074/jbc.270.41.24604. PMID 7592681. S2CID 23576318.
• Shintani S, Funayama T, Yoshihama Y, et al. (1995). "Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma". Cancer Lett. 95 (1–2): 79–83. doi:10.1016/0304-3835(95)03866-U. PMID 7656248.
• Katoh M, Yazaki Y, Sugimura T, Terada M (1993). "c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase". Biochem. Biophys. Res. Commun. 192 (3): 1189–97. doi:10.1006/bbrc.1993.1542. PMID 7685162.
• Culouscou JM, Plowman GD, Carlton GW, et al. (1993). "Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor". J. Biol. Chem. 268 (25): 18407–10. doi:10.1016/S0021-9258(17)46636-1. PMID 7689552.
• Zelada-Hedman M, Werer G, Collins P, et al. (1995). "High expression of the EGFR in fibroadenomas compared to breast carcinomas". Anticancer Res. 14 (5A): 1679–88. PMID 7847801.
• Shintani S, Funayama T, Yoshihama Y, et al. (1996). "Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study". Anticancer Res. 15 (6B): 2623–6. PMID 8669836.
• Chang H, Riese DJ, Gilbert W, et al. (1997). "Ligands for ErbB-family receptors encoded by a neuregulin-like gene". Nature. 387 (6632): 509–12. doi:10.1038/387509a0. PMID 9168114. S2CID 4359654.
• Fiddes RJ, Campbell DH, Janes PW, et al. (1998). "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3". J. Biol. Chem. 273 (13): 7717–24. doi:10.1074/jbc.273.13.7717. PMID 9516479. S2CID 22017882.
• Jones JT, Ballinger MD, Pisacane PI, et al. (1998). "Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis". J. Biol. Chem. 273 (19): 11667–74. doi:10.1074/jbc.273.19.11667. PMID 9565587. S2CID 42404398.
• Lee H, Maihle NJ (1998). "Isolation and characterization of four alternate c-erbB3 transcripts expressed in ovarian carcinoma-derived cell lines and normal human tissues". Oncogene. 16 (25): 3243–52. doi:10.1038/sj.onc.1201866. PMID 9681822. S2CID 9785761.
• Vijapurkar U, Cheng K, Koland JG (1998). "Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase". J. Biol. Chem. 273 (33): 20996–1002. doi:10.1074/jbc.273.33.20996. PMID 9694850. S2CID 9469356.
• Yoo JY, Hamburger AW (1999). "Interaction of the p23/p198 protein with ErbB-3". Gene. 229 (1–2): 215–21. doi:10.1016/S0378-1119(98)00604-0. PMID 10095121.
• Lin J, Adam RM, Santiestevan E, Freeman MR (1999). "The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells". Cancer Res. 59 (12): 2891–7. PMID 10383151.