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ErbB2/HER2/Neu resembles an autoinhibited invertebrate EGF receptor
Author(s) -
Alvarado Diego,
Klein Daryl E,
Lemmon Mark A
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.884.3
Subject(s) - receptor tyrosine kinase , erbb , ror1 , microbiology and biotechnology , receptor , biology , drosophila melanogaster , tyrosine kinase , signal transduction , extracellular , biochemistry , gene , platelet derived growth factor receptor , growth factor
The orphan receptor tyrosine kinase ErbB2 (HER2/Neu) is potently transforming upon overexpression, and is an important therapeutic target in human cancer. ErbB2 lacks a key autoinhibitory 'tether' in its extracellular region that is present in other human ErbB receptors (including the EGF receptor), providing a potential explanation for its oncogenic properties and activity. Here, we present structural studies of the tightly ligand‐regulated Drosophila melanogaster EGFR (dEGFR) that challenge the notion that ErbB2 lacks autoinhibition. Inactive dEGFR is stabilized by a set of interdomain interactions distinct from the 'tether' in human EGFR. Surprisingly, all of these autoinhibitory interactions in the unliganded dEGFR structure are maintained (and even extended) in ErbB2. This similarity to dEGFR argues that normal and pathogenic ErbB2 signaling may also be ligand‐regulated. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches to target novel aspects of this orphan receptor.