ERBB3

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V-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)
Protein ERBB3 PDB 1m6b.png
PDB rendering based on 1m6b.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ERBB3 ; ErbB-3; HER3; LCCS2; MDA-BF-1; c-erbB-3; c-erbB3; erbB3-S; p180-ErbB3; p45-sErbB3; p85-sErbB3
External IDs OMIM190151 MGI95411 HomoloGene20457 ChEMBL: 5838 GeneCards: ERBB3 Gene
EC number 2.7.10.1
RNA expression pattern
PBB GE ERBB3 202454 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2065 13867
Ensembl ENSG00000065361 ENSMUSG00000018166
UniProt P21860 Q61526
RefSeq (mRNA) NM_001005915 NM_010153
RefSeq (protein) NP_001005915 NP_034283
Location (UCSC) Chr 12:
56.47 – 56.5 Mb
Chr 10:
128.57 – 128.59 Mb
PubMed search [1] [2]

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.[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[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.[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.[5]

Function[edit]

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 transphosporylation by its binding partner to be active.[5]

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 1/1000th the autophosphorylation activity of EGFR and no ability to phosphorylate other proteins.[8] 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.[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]

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.[13] ErbB3 binding causes the allosteric activation of p110, the lipid kinase subunit of PI3K,[10] 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,[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]

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.[10]

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. Interestingly, while this function of ErbB3 depends of neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue.[24]

ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system [25] and neural crest derivatives such as Schwann cells.[26]

See also[edit]

References[edit]

  1. ^ "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 (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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ a b c 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. 
  6. ^ 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. PMID 8188716. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. PMC 231527. PMID 8816440. 
  10. ^ a b c 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. 
  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 (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. 
  12. ^ 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. 
  13. ^ 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. PMC 395164. PMID 8026468. 
  14. ^ 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. 
  15. ^ 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. PMID 12853564. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. PMID 17203234. 
  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 (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. 
  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 (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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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. 
  25. ^ 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. PMID 9637684. 
  26. ^ 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. 

Further reading[edit]