ErbB

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Overview

The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. 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

The ErbB protein family consists of 4 members

Structure

ErbB receptors are made up of an extracellular region which 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, were "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).[5][6][2][7]

File:Erb fig.jpeg
Comparison of ErbB extracellular domain structures

Kinase activation

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]


.


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 - - - +

Role in cancer

ErbB-1 is overexpressed in many cancers. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit it. It has recently been shown that acquired resistance to the two first can be linked to hyperactivity of ErbB-3.[9] This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway.[10]

References

  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. PMID 17314037.
  2. 2.0 2.1 Cho HS and Leahy DJ. (2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–1333. PMID 12154198.
  3. 3.0 3.1 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. 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. 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. 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. 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. PMID 16203964.
  8. Linggi, B. and Carpenter, G. (2006). "ErbB receptors: new insights on mechanisms and biology". Trends Cell Biol. 16 (12): 649–656. PMID 17085050.
  9. 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. PMID 17463250.
  10. "Cancer therapies addressing HGF/c-Met". Retrieved 2007-10-02.



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