ErbB


ErbB

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.cite journal | author = Bublil EM and Yarden Y. | title = The EGF receptor family: spearheading a merger of signaling and therapeutics | journal = Curr. Opin. Cell Biol. | year=2007 | volume=19 | issue=2 | pages=124–134 | pmid = 17314037 | doi = 10.1016/j.ceb.2007.02.008] 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.cite journal | author = Cho HS and Leahy DJ. | title = Structure of the extracellular region of HER3 reveals an interdomain tether | journal = Science | year=2002 | volume=297 | issue=5585 | pages=1330–1333 | pmid = 12154198 | doi = 10.1126/science.1074611]

Family members

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 and
* ErbB-4, also named HER4

tructure

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.cite journal | author = Garrett, T. P. J., McKern, N. M. "et al."| title = Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α | journal = Cell | year=2002 | volume=110 | issue=6 | pages=763–773 | pmid = 12297049| doi = 10.1016/S0092-8674(02)00940-6] cite journal | author = Ward CW., Lawrence M.C. "et al" | title = The insulin and EGF receptor structures: new insights into ligand-induced receptor activation | journal = Trends Biochem. Sci. | year=2007 | volume=32 | issue=3 | pages=129–137 | pmid = 17280834 | doi = 10.1016/j.tibs.2007.01.001] The figure below was created using the pdb files [http://www.pdb.org/pdb/explore/explore.do?structureId=1NQL 1NQL] (ErbB-1), [http://www.pdb.org/pdb/explore/explore.do?structureId=1S78 1S78] (ErbB-2), [http://www.pdb.org/pdb/explore/explore.do?structureId=1M6B 1M6B] (ErbB-3) and [http://www.pdb.org/pdb/explore/explore.do?structureId=2AHX 2AHX] (ErbB-4).cite journal | author = Ferguson KM, Berger MB, "et al" | title = EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization | journal = Mol. Cell. | year=2003 | volume=11 | issue=2 | pages=507–517 | pmid = 12620237 | doi = 10.1016/S1097-2765(03)00047-9] cite journal | author = Franklin MC, Carey KD "et al" | title = Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex | journal = Cancer Cell. | year=2004 | volume=5 | issue=4 | pages=317–328 | pmid = 15093539 | doi = 10.1016/S1535-6108(04)00083-2] cite journal | author = Bouyain S, Longo PA, "et al." | title = The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand | journal = Proc. Natl. Acad. Sci. USA. | year=2005 | volume=102 | issue=42 | pages=15024–15029 | pmid = 16203964 | doi = 10.1073/pnas.0507591102]

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. 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.cite journal | author = Linggi, B. and Carpenter, G.| title = ErbB receptors: new insights on mechanisms and biology | journal = Trends Cell Biol. | year=2006 | volume=16 | issue=12 | pages=649–656 | pmid = 17085050| doi = 10.1016/j.tcb.2006.10.008]

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.cite journal | author = Engelman J.A., Zejnullahu K. "et al"| title = MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling | journal = Science | year=2007 | volume=316 | issue=5827 | pages=1039–1043 | pmid = 17463250| doi = 10.1126/science.1141478] This is linked to an acquired overexpression of c-MET which phosphorylates ErbB-3, which in turn activates the Akt pathway. [cite web | title = Cancer therapies addressing HGF/c-Met | url = http://www.healthvalue.net/cmettherapies.html | accessdate = 2007-10-02]

References


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