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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, VSCN1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 190151; MGI: 95411; HomoloGene: 20457; GeneCards: ERBB3; OMA:ERBB3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018166 – Ensembl, May 2017
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- ^ 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.
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Further reading
[edit]- 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. Bibcode:1990PNAS...87.4905P. 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. Bibcode:1997Natur.387R.509C. 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.
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