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The ErbB/HER receptor protein-tyrosine kinases and cancer
Authors:Roskoski Robert
Institution:Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1100 Florida Avenue, New Orleans, LA 70119, USA. biocrr@lsuhsc.edu
Abstract:The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, consist of a growth-factor-binding ectodomain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. The genes for the four members of this family, ErbB1-ErbB4, are found on different human chromosomes. Null mutations of any of the ErbB family members result in embryonic lethality. ErbB1 and ErbB2 are overexpressed in a wide variety of tumors including breast, colorectal, ovarian, and non-small cell lung cancers. The structures of the ectodomains of the ErbB receptors in their active and inactive conformation have shed light on the mechanism of receptor activation. The extracellular component of the ErbB proteins consists of domains I-IV. The activating growth factor, which binds to domains I and III, selects and stabilizes a conformation that allows a dimerization arm to extend from domain II to interact with an ErbB dimer partner. As a result of dimerization, protein kinase activation, trans-autophosphorylation, and initiation of signaling occur. The conversion of the inactive to active receptor involves a major rotation of the ectodomain. The ErbB receptors are targets for anticancer drugs. Two strategies for blocking the action of these proteins include antibodies directed against the ectodomain and drugs that inhibit protein-tyrosine kinase activity. A reversible ATP competitive inhibitor of ErbB1 (ZD1839, or Iressa) and an ErbB1 ectodomain directed antibody (IMC-C225, or Erbitux) have been approved for the treatment of non-small cell lung cancer and colorectal cancer, respectively. An ErbB2/HER2 ectodomain directed antibody (trastuzumab, or Herceptin) has also been approved for the treatment of breast cancer. Current research promises to produce additional agents based upon these approaches.
Keywords:Bcr-Abl  Breast cancer  Cetuximab  Chronic myelogenous leukemia  Colorectal cancer  CP-358  774  Epidermal growth factor  Erbitux  ERK  Erlotinib  Gefitinib  Gleevec  Herceptin  IMC-C225  Irressa  K-ras  MEK  Monoclonal antibody  Non-small cell lung cancer  OSI-774  Phospholipase Cγ  Phosphoserine  Phosphothreonine  Phosphotyrosine  Protein kinase A  Protein kinase C  Raf  STI-571  Tarceva  Trastuzumab  ZD1839
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