ERBB3 explained

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 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.^[1]

During human development, ERBB3 is expressed in skin, bone, muscle, nervous system, heart, lungs, and intestinal epithelium.^[2] ERBB3 is expressed in normal adult human gastrointestinal tract, reproductive system, skin, nervous system, urinary tract, and endocrine system.^[3]

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.^[4] The cytoplasmic domain contains a juxtamembrane segment, a kinase domain, and a C-terminal domain.^[5]

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.

Function

ErbB3 has been shown to bind the ligands heregulin^[6] and NRG-2.^[7] 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.

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.^[8] 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.^[9] This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ.^[10] There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands.^{[11] [12]}

The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K.^[13] ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K, 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,^[14] the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis.^{[15] [16]}

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

• HER2 inhibitors in HER2+ breast cancers^[17]
• anti-estrogen therapy in ER⁺ breast cancers^{[18] [19]}
• EGFR inhibitors in lung and head and neck cancers^{[20] [21]}
• hormones in prostate cancers^[22]
• IGF1R inhibitors in hepatomas^[23]
• BRAF inhibitors in melanoma^[24]

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.

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.^[25]

ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system^[26] and neural crest derivatives such as Schwann cells.^[27]

See also

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

Further reading

• Corfas G, Roy K, Buxbaum JD . Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia . Nat. Neurosci. . 7 . 6 . 575–80 . 2004 . 15162166 . 10.1038/nn1258 . 10692780 .
• Plowman GD, Whitney GS, Neubauer MG . Molecular cloning and expression of an additional epidermal growth factor receptor-related gene . Proc. Natl. Acad. Sci. U.S.A. . 87 . 13 . 4905–9 . 1990 . 2164210 . 10.1073/pnas.87.13.4905 . 54229 . 1990PNAS...87.4905P . etal. free .
• Kraus MH, Issing W, Miki T . 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 . 1990 . 2687875 . 10.1073/pnas.86.23.9193 . 298460 . etal. free .
• Alimandi M, Romano A, Curia MC . Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas . Oncogene . 10 . 9 . 1813–21 . 1995 . 7538656 . etal.
• Wallasch C, Weiss FU, Niederfellner G . Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3 . EMBO J. . 14 . 17 . 4267–75 . 1995 . 7556068 . 10.1002/j.1460-2075.1995.tb00101.x. 394510 . etal.
• Horan T, Wen J, Arakawa T . Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3 . J. Biol. Chem. . 270 . 41 . 24604–8 . 1995 . 7592681 . 10.1074/jbc.270.41.24604 . 23576318 . etal. free .
• Shintani S, Funayama T, Yoshihama Y . Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma . Cancer Lett. . 95 . 1–2 . 79–83 . 1995 . 7656248 . 10.1016/0304-3835(95)03866-U . etal.
• Katoh M, Yazaki Y, Sugimura T, Terada M . c-erbB3 gene encodes secreted as well as transmembrane receptor tyrosine kinase . Biochem. Biophys. Res. Commun. . 192 . 3 . 1189–97 . 1993 . 7685162 . 10.1006/bbrc.1993.1542 .
• Culouscou JM, Plowman GD, Carlton GW . Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor . J. Biol. Chem. . 268 . 25 . 18407–10 . 1993 . 10.1016/S0021-9258(17)46636-1 . 7689552 . etal. free .
• Zelada-Hedman M, Werer G, Collins P . High expression of the EGFR in fibroadenomas compared to breast carcinomas . Anticancer Res. . 14 . 5A . 1679–88 . 1995 . 7847801 . etal.
• Shintani S, Funayama T, Yoshihama Y . Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study . Anticancer Res. . 15 . 6B . 2623–6 . 1996 . 8669836 . etal.
• Chang H, Riese DJ, Gilbert W . Ligands for ErbB-family receptors encoded by a neuregulin-like gene . Nature . 387 . 6632 . 509–12 . 1997 . 9168114 . 10.1038/387509a0 . 1997Natur.387R.509C . 4359654 . etal.
• Fiddes RJ, Campbell DH, Janes PW . Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3 . J. Biol. Chem. . 273 . 13 . 7717–24 . 1998 . 9516479 . 10.1074/jbc.273.13.7717 . 22017882 . etal. free .
• Jones JT, Ballinger MD, Pisacane PI . Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis . J. Biol. Chem. . 273 . 19 . 11667–74 . 1998 . 9565587 . 10.1074/jbc.273.19.11667 . 42404398 . etal. free .
• Lee H, Maihle NJ . 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 . 1998 . 9681822 . 10.1038/sj.onc.1201866 . 9785761 . free .
• Vijapurkar U, Cheng K, Koland JG . 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 . 1998 . 9694850 . 10.1074/jbc.273.33.20996 . 9469356 . free .
• Yoo JY, Hamburger AW . Interaction of the p23/p198 protein with ErbB-3 . Gene . 229 . 1–2 . 215–21 . 1999 . 10095121 . 10.1016/S0378-1119(98)00604-0 .
• Lin J, Adam RM, Santiestevan E, Freeman MR . 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 . 1999 . 10383151 .

Notes and References

1. Web site: ERBB3 Gene – GeneCards ERBB3 Protein .
2. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U . Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene . Science . 230 . 4730 . 1132–9 . 1985 . 2999974 . 10.1126/science.2999974. 1985Sci...230.1132C .
3. Prigent SA, Lemoine NR, Hughes CM, Plowman GD, Selden C, Gullick WJ . Expression of the c-erbB-3 protein in normal human adult and fetal tissues . Oncogene . 7 . 7 . 1273–8 . 1992 . 1377811 .
4. Cho HS, Leahy DJ . Structure of the extracellular region of HER3 reveals an interdomain tether . Science . 297 . 5585 . 1330–3 . 2002 . 12154198 . 10.1126/science.1074611 . 2002Sci...297.1330C . 23069349 . free .
5. Roskoski R . The ErbB/HER family of protein-tyrosine kinases and cancer . Pharmacol. Res. . 79 . 34–74 . 2014 . 24269963 . 10.1016/j.phrs.2013.11.002 .
6. Carraway KL, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA . The erbB3 gene product is a receptor for heregulin . J. Biol. Chem. . 269 . 19 . 14303–6 . 1994 . 10.1016/S0021-9258(17)36789-3 . 8188716 . free .
7. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C . Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases . Nature . 387 . 6632 . 512–6 . 1997 . 9168115 . 10.1038/387512a0 . 1997Natur.387R.512C . 4310136 .
8. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA . ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation . Proc. Natl. Acad. Sci. U.S.A. . 107 . 17 . 7692–7 . 2010 . 20351256 . 2867849 . 10.1073/pnas.1002753107 . 2010PNAS..107.7692S . free .
9. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y . 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 . 1996 . 8816440 . 231527 . 10.1128/MCB.16.10.5276.
10. Citri A, Skaria KB, Yarden Y . The deaf and the dumb: the biology of ErbB-2 and ErbB-3 . Exp. Cell Res. . 284 . 1 . 54–65 . 2003 . 12648465 . 10.1016/s0014-4827(02)00101-5.
11. Pinkas-Kramarski R, Lenferink AE, Bacus SS, Lyass L, van de Poll ML, Klapper LN, Tzahar E, Sela M, van Zoelen EJ, Yarden Y . The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin . Oncogene . 16 . 10 . 1249–58 . 1998 . 9546426 . 10.1038/sj.onc.1201642 . 25652800 .
12. Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M, Fedi P, Tang C, Lippman M, Pierce JH . Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors . EMBO J. . 16 . 18 . 5608–17 . 1997 . 9312020 . 1170193 . 10.1093/emboj/16.18.5608 .
13. Prigent SA, Gullick WJ . 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 . 1994 . 8026468 . 395164 . 10.1002/j.1460-2075.1994.tb06577.x.
14. Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A, Yoshinaga SK . Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2 . J. Biol. Chem. . 271 . 7 . 3884–90 . 1996 . 8632008 . 10.1074/jbc.271.7.3884. 7190224 . free .
15. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE . 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 . 2003 . 12853564 . 10.1073/pnas.1537685100 . 166416. 2003PNAS..100.8933H . free .
16. Wang S, Huang X, Lee CK, Liu B . Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin . Oncogene . 29 . 29 . 4225–36 . 2010 . 20498641 . 10.1038/onc.2010.180 . 22169790 . free .
17. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM . Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3 . Nature . 445 . 7126 . 437–41 . 2007 . 17206155 . 3025857 . 10.1038/nature05474 . 2007Natur.445..437S .
18. Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, Jordan VC . Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer . Int. J. Oncol. . 30 . 2 . 509–20 . 2007 . 17203234 . 10.3892/ijo.30.2.509. 31 January 2024 .
19. 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 . 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 . 2009 . 19435893 . 2724871 . 10.1158/0008-5472.CAN-09-0042 .
20. 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 . MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling . Science . 316 . 5827 . 1039–43 . 2007 . 17463250 . 10.1126/science.1141478 . 2007Sci...316.1039E . 23254145 . free .
21. Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P, Kulmala J, Pulkkinen J, Grenman R, Elenius K . 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 . 2006 . 16818711 . 10.1158/1078-0432.CCR-05-2404 . 5571305 . free .
22. Zhang Y, Linn D, Liu Z, Melamed J, Tavora F, Young CY, Burger AM, Hamburger AW . EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance . Mol. Cancer Ther. . 7 . 10 . 3176–86 . 2008 . 18852121 . 2629587 . 10.1158/1535-7163.MCT-08-0526 .
23. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël MJ, Fartoux L, Venot C, Bladt F, Housset C, Rosmorduc O . 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 . 2009 . 19706799 . 10.1158/1078-0432.CCR-08-2980 . 207699374 . free .
24. Function-Blocking ERBB3 Antibody Inhibits the Adaptive Response to RAF Inhibitor. July 17, 2014. The Journal of Cancer Research. 74. 15. 4122–4132. 10.1158/0008-5472.CAN-14-0464. 25035390. 4120074. Kugel. C. H.. Hartsough. E. J.. Davies. M. A.. Setiady. Y. Y.. Aplin. A. E..
25. Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C . Severe neuropathies in mice with targeted mutations in the ErbB3 receptor . Nature . 389 . 6652 . 725–30 . 1997 . 9338783 . 10.1038/39593 . 1997Natur.389..725R . 28741273 .
26. Britsch. S. Li, L . Kirchhoff, S . Theuring, F . Brinkmann, V . Birchmeier, C . Riethmacher, D . The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system.. Genes & Development. 1998. 12. 12. 1825–36. 9637684. 10.1101/gad.12.12.1825 . 316903.
27. Davies AM . Neuronal survival: early dependence on Schwann cells . Curr. Biol. . 8 . 1 . R15–8 . 1998 . 9427620 . 10.1016/s0960-9822(98)70009-0. 2745201 . free . 1998CBio....8..R15D .