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 (EGFR, ErbB1), Her2 (Neu, 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.
In mice, loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart, and brain. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers, and their excessive signaling may be critical factors in the development and malignancy of these tumors.
The ErbB protein family consists of 4 members
- ErbB-1, also named epidermal growth factor receptor (EGFR)
- ErbB-2, also named HER2 in humans and neu in rodents
- ErbB-3, also named HER3
- ErbB-4, also named HER4
v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.
ErbB receptors are made up of an extracellular region or ectodomain that contains approximately 620 amino acids, a single transmembrane-spanning region, and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2), and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV, respectively.
The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher-order oligomers upon activation by a subset of potential growth factor ligands. There are 11 growth factors that activate ErbB receptors.
The ability ('+') or inability ('-') of each growth factor to activate each of the ErbB receptors is shown in the table below:
When not bound to a ligand, the extracellular regions of ErbB-1, -3, and -4 are found in a tethered conformation in which a 10-amino-acid-long dimerisation arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerisation arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. The consequence of ectodomain dimerisation is the positioning of two cytoplasmic domains such that transphosphorylation of specific tyrosine, serine, and threonine amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within the cytoplamic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerisation. Although a number of potential phosphorylation sites exist, upon dimerisation only one or much more rarely two of these sites are phosphorylated at any one time.
Role in cancer
Phosphorylated tyrosine residues act as binding sites for intracellular signal activators such as Ras. The Ras-Raf-MAPK pathway is a major signalling route for the ErbB family, as is the PI3-K/AKT pathway, both of which lead to increased cell proliferation and inhibition of apoptosis.
ErbB-1 is overexpressed in many cancers. Drugs such as panitumumab, cetuximab, gefitinib, erlotinib, afatinib are used to inhibit it. It has recently been shown that acquired resistance to cetuximab and gefitinib can be linked to hyperactivity of ErbB-3. This is linked to an acquired overexpression of c-MET, which phosphorylates ErbB-3, which in turn activates the AKT pathway.
ErbB-2 (HER-2) is often overexpressed in breast cancer, and is targeted by the drug trastuzumab (Herceptin). Only one-third of the women respond to trastuzumab. While the mechanism of resistance has not yet been elucidated, it has been shown that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.
- Bublil EM, Yarden Y (April 2007). "The EGF receptor family: spearheading a merger of signaling and therapeutics". Current Opinion in Cell Biology. 19 (2): 124–34. doi:10.1016/j.ceb.2007.02.008. PMID 17314037.
- Cho HS, Leahy DJ (August 2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–3. doi:10.1126/science.1074611. PMID 12154198.
- Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, et al. (September 2002). "Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha". Cell. 110 (6): 763–73. doi:10.1016/S0092-8674(02)00940-6. PMID 12297049.
- Ward CW, Lawrence MC, Streltsov VA, Adams TE, McKern NM (March 2007). "The insulin and EGF receptor structures: new insights into ligand-induced receptor activation". Trends in Biochemical Sciences. 32 (3): 129–37. doi:10.1016/j.tibs.2007.01.001. PMID 17280834.
- Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA (February 2003). "EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization". Molecular Cell. 11 (2): 507–17. doi:10.1016/S1097-2765(03)00047-9. PMID 12620237.
- Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (April 2004). "Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex". Cancer Cell. 5 (4): 317–28. doi:10.1016/S1535-6108(04)00083-2. PMID 15093539.
- Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ (October 2005). "The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand". Proceedings of the National Academy of Sciences of the United States of America. 102 (42): 15024–9. doi:10.1073/pnas.0507591102. PMC . PMID 16203964.
- Linggi B, Carpenter G (December 2006). "ErbB receptors: new insights on mechanisms and biology". Trends in Cell Biology. 16 (12): 649–56. doi:10.1016/j.tcb.2006.10.008. PMID 17085050.
- Wu SL, Kim J, Bandle RW, Liotta L, Petricoin E, Karger BL (September 2006). "Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using Extended Range Proteomic Analysis (ERPA)". Molecular & Cellular Proteomics. 5 (9): 1610–27. doi:10.1074/mcp.M600105-MCP200. PMID 16799092.
- Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Molecular Systems Biology. 1 (2005.0008): 2005.0008. doi:10.1038/msb4100012. PMC . PMID 16729043.
- Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (March 2003). "Epidermal growth factor receptor: mechanisms of activation and signalling". Experimental Cell Research. 284 (1): 31–53. doi:10.1016/S0014-4827(02)00098-8. PMID 12648464.
- Herbst, RS (2004). "Review of epidermal growth factor receptor biology". International Journal of Radiation Oncology. 59 (2).
- 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 (May 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.
- "Cancer therapies addressing HGF/c-Met". Retrieved 2007-10-02.
- Chung A, Cui X, Audeh W, Giuliano A (2013). "Current status of anti-human epidermal growth factor receptor 2 therapies: predicting and overcoming herceptin resistance". Clinical Breast Cancer. 13 (4): 223–32. doi:10.1016/j.clbc.2013.04.001. PMC . PMID 23829888.