ERBB3

Last updated

ERBB3
Protein ERBB3 PDB 1m6b.png
Available structures
PDB Ortholog search: PDBe RCSB
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, VSCN1
External IDs OMIM: 190151; MGI: 95411; HomoloGene: 20457; GeneCards: ERBB3; OMA:ERBB3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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: 128.4 – 128.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [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:

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

Related Research Articles

<span class="mw-page-title-main">Tyrosine kinase</span> Enzyme

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

<span class="mw-page-title-main">Gefitinib</span> Medication used for cancer

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Epidermal growth factor</span> Protein that stimulates cell division and differentiation

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

<span class="mw-page-title-main">Neuregulin</span> Family of four EGF proteins

Neuregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.

<span class="mw-page-title-main">Erlotinib</span> Medication for treatment of non-small-cell lung cancer

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">GRB7</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 7, also known as GRB7, is a protein that in humans is encoded by the GRB7 gene.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma of the head and neck (SCCHN), a type of cancer.

<span class="mw-page-title-main">Neuregulin 1</span> Protein-coding gene in the species Homo sapiens

Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">Epiregulin</span> Protein found in humans

Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.

<span class="mw-page-title-main">ERBB4</span> Protein-coding gene in the species Homo sapiens

Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized.

<span class="mw-page-title-main">Neuregulin 2</span> Protein-coding gene in the species Homo sapiens

Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.

<span class="mw-page-title-main">Neuregulin 4</span> Protein-coding gene in the species Homo sapiens

Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.

<span class="mw-page-title-main">Tyrosine kinase inhibitor</span> Drug typically used in cancer treatment

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000065361 Ensembl, May 2017
  2. 1 2 3 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, et al. (December 1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science. 230 (4730): 1132–1139. Bibcode:1985Sci...230.1132C. doi:10.1126/science.2999974. PMID   2999974.
  7. Prigent SA, Lemoine NR, Hughes CM, Plowman GD, Selden C, Gullick WJ (July 1992). "Expression of the c-erbB-3 protein in normal human adult and fetal tissues". Oncogene. 7 (7): 1273–1278. PMID   1377811.
  8. Cho HS, Leahy DJ (August 2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–1333. Bibcode:2002Sci...297.1330C. doi: 10.1126/science.1074611 . PMID   12154198. S2CID   23069349.
  9. 1 2 3 Roskoski R (January 2014). "The ErbB/HER family of protein-tyrosine kinases and cancer". Pharmacological Research. 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, et al. (May 1994). "The erbB3 gene product is a receptor for heregulin". The Journal of Biological Chemistry. 269 (19): 14303–14306. doi: 10.1016/S0021-9258(17)36789-3 . PMID   8188716.
  11. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, et al. (May 1997). "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases". Nature. 387 (6632): 512–516. Bibcode:1997Natur.387R.512C. doi:10.1038/387512a0. PMID   9168115. S2CID   4310136.
  12. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA (April 2010). "ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation". Proceedings of the National Academy of Sciences of the United States of America. 107 (17): 7692–7697. Bibcode:2010PNAS..107.7692S. doi: 10.1073/pnas.1002753107 . PMC   2867849 . PMID   20351256.
  13. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, et al. (October 1996). "A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor". Molecular and Cellular Biology. 16 (10): 5276–5287. doi:10.1128/MCB.16.10.5276. PMC   231527 . PMID   8816440.
  14. 1 2 3 Citri A, Skaria KB, Yarden Y (March 2003). "The deaf and the dumb: the biology of ErbB-2 and ErbB-3". Experimental Cell Research. 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, et al. (March 1998). "The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin". Oncogene. 16 (10): 1249–1258. doi:10.1038/sj.onc.1201642. PMID   9546426. S2CID   25652800.
  16. Alimandi M, Wang LM, Bottaro D, Lee CC, Kuo A, Frankel M, et al. (September 1997). "Epidermal growth factor and betacellulin mediate signal transduction through co-expressed ErbB2 and ErbB3 receptors". The EMBO Journal. 16 (18): 5608–5617. doi:10.1093/emboj/16.18.5608. PMC   1170193 . PMID   9312020.
  17. Prigent SA, Gullick WJ (June 1994). "Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera". The EMBO Journal. 13 (12): 2831–2841. 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, et al. (February 1996). "Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2". The Journal of Biological Chemistry. 271 (7): 3884–3890. doi: 10.1074/jbc.271.7.3884 . PMID   8632008. S2CID   7190224.
  19. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE (July 2003). "The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation". Proceedings of the National Academy of Sciences of the United States of America. 100 (15): 8933–8938. Bibcode:2003PNAS..100.8933H. doi: 10.1073/pnas.1537685100 . PMC   166416 . PMID   12853564.
  20. Wang S, Huang X, Lee CK, Liu B (July 2010). "Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin". Oncogene. 29 (29): 4225–4236. doi: 10.1038/onc.2010.180 . PMID   20498641. S2CID   22169790.
  21. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. (January 2007). "Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3". Nature. 445 (7126): 437–441. Bibcode:2007Natur.445..437S. doi:10.1038/nature05474. PMC   3025857 . PMID   17206155.
  22. Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, et al. (February 2007). "Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer". International Journal of Oncology. 30 (2): 509–520. doi:10.3892/ijo.30.2.509 (inactive 2024-09-12). PMID   17203234.{{cite journal}}: CS1 maint: DOI inactive as of September 2024 (link)
  23. Miller TW, Pérez-Torres M, Narasanna A, Guix M, Stål O, Pérez-Tenorio G, et al. (May 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 Research. 69 (10): 4192–4201. 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, et al. (May 2007). "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling". Science. 316 (5827): 1039–1043. Bibcode:2007Sci...316.1039E. doi: 10.1126/science.1141478 . PMID   17463250. S2CID   23254145.
  25. Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P, et al. (July 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". Clinical Cancer Research. 12 (13): 4103–4111. 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, et al. (October 2008). "EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance". Molecular Cancer Therapeutics. 7 (10): 3176–3186. 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, et al. (September 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". Clinical Cancer Research. 15 (17): 5445–5456. doi: 10.1158/1078-0432.CCR-08-2980 . PMID   19706799. S2CID   207699374.
  28. Kugel CH, Hartsough EJ, Davies MA, Setiady YY, Aplin AE (August 2014). "Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor". 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 (October 1997). "Severe neuropathies in mice with targeted mutations in the ErbB3 receptor". Nature. 389 (6652): 725–730. Bibcode:1997Natur.389..725R. doi:10.1038/39593. PMID   9338783. S2CID   28741273.
  30. Britsch S, Li L, Kirchhoff S, Theuring F, Brinkmann V, Birchmeier C, et al. (June 1998). "The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system". Genes & Development. 12 (12): 1825–1836. doi:10.1101/gad.12.12.1825. PMC   316903 . PMID   9637684.
  31. Davies AM (January 1998). "Neuronal survival: early dependence on Schwann cells". Current Biology. 8 (1): R15–R18. Bibcode:1998CBio....8..R15D. doi: 10.1016/s0960-9822(98)70009-0 . PMID   9427620. S2CID   2745201.

Further reading