ErbB

From Wikipedia, the free encyclopedia
Jump to: navigation, search

The epidermal growth factor receptor (EGFR) is the founding member of the ErbB family of four structurally related receptor tyrosine kinases. In humans this 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.[1] 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.[2]

Family members[edit]

The ErbB protein family consists of 4 members

v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.

Structure[edit]

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.[3][4] The figure below was created using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).[2][5][6][7]

Comparison of ErbB extracellular domain structures

Kinase activation[edit]

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.[3] There are 11 growth factors that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.[8]

A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer (as shown) activates the kinase at the bottom of each dimer (Zhang et al., Cell v. 125, pp. 1137-1149, 2008). The cluster was identified with the ProtCID database. The image was made with PyMOL.
Ligand Receptor
ErbB-1 ErbB-2 ErbB-3 ErbB-4
EGF + - - -
TGF-α + - - -
HB-EGF + - - +
amphiregulin + - - -
betacellulin + - - +
epigen + - - -
epiregulin + - - +
neuregulin 1 - - + +
neuregulin 2 - - + +
neuregulin 3 - - - +
neuregulin 4 - - - +

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.[8] The consequence of ectodomain dimerisation is the positioning of two cytoplasmic domain 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.[9][10][11] 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.[9]

Role in cancer[edit]

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.[12] This is linked to an acquired overexpression of c-MET, which phosphorylates ErbB-3, which in turn activates the Akt pathway.[13] ErbB-2 (HER-2) is often overexpressed in breast cancer. The drug trastuzumab (Herceptin) targets this receptor. Only one-third of the women respond to Trastuzumab, and recently it was not known what causes the resistance 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.[14]

References[edit]

  1. ^ Bublil EM and Yarden Y. (2007). "The EGF receptor family: spearheading a merger of signaling and therapeutics". Curr. Opin. Cell Biol. 19 (2): 124–134. doi:10.1016/j.ceb.2007.02.008. PMID 17314037. 
  2. ^ a b Cho HS and Leahy DJ. (2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science 297 (5585): 1330–1333. doi:10.1126/science.1074611. PMID 12154198. 
  3. ^ a b Garrett, T. P. J., McKern, N. M. et al. (2002). "Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α". Cell 110 (6): 763–773. doi:10.1016/S0092-8674(02)00940-6. PMID 12297049. 
  4. ^ Ward CW., Lawrence M.C. et al (2007). "The insulin and EGF receptor structures: new insights into ligand-induced receptor activation". Trends Biochem. Sci. 32 (3): 129–137. doi:10.1016/j.tibs.2007.01.001. PMID 17280834. 
  5. ^ Ferguson KM, Berger MB, et al (2003). "EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization". Mol. Cell. 11 (2): 507–517. doi:10.1016/S1097-2765(03)00047-9. PMID 12620237. 
  6. ^ Franklin MC, Carey KD et al (2004). "Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex". Cancer Cell. 5 (4): 317–328. doi:10.1016/S1535-6108(04)00083-2. PMID 15093539. 
  7. ^ Bouyain S, Longo PA, et al. (2005). "The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand". Proc. Natl. Acad. Sci. USA. 102 (42): 15024–15029. doi:10.1073/pnas.0507591102. PMC 1257738. PMID 16203964. 
  8. ^ a b Linggi, B. and Carpenter, G. (2006). "ErbB receptors: new insights on mechanisms and biology". Trends Cell Biol. 16 (12): 649–656. doi:10.1016/j.tcb.2006.10.008. PMID 17085050. 
  9. ^ a b Wu SL, Kim J, et al. (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)". Mol. Cell Proteomics. 5 (9): 1610–1627. doi:10.1074/mcp.M600105-MCP200. PMID 16799092. 
  10. ^ Schulze WX, Deng L, Mann M. (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1 (2005.0008): 2005.0008. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043. 
  11. ^ Jorissen RN, Walker F, et al. (2003). "Epidermal growth factor receptor: mechanisms of activation and signalling". Exp. Cell Res. 284 (10): 31–53. doi:10.1016/S0014-4827(02)00098-8. PMID 12648464. 
  12. ^ Engelman J.A., Zejnullahu K. et al (2007). "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling". Science 316 (5827): 1039–1043. doi:10.1126/science.1141478. PMID 17463250. 
  13. ^ "Cancer therapies addressing HGF/c-Met". Retrieved 2007-10-02. 
  14. ^ Estrogen Receptor Status of HER2+ Breast Cancer Correlates With Response to Anti-HER Therapies. ScienceDaily (May 6, 2010)[1]