SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes.
Based on the presence of multiple proline-rich motifs in the huntingtin sequence, we tested its possible association with epidermal growth factor (EGF) receptor signaling complexes through SH3 domain-containing modules. We found that huntingtin is associated with Grb2, RasGAP, and tyrosine-phosphorylated EGF receptor. These associations are regulated by activation of the EGF receptor, suggesting that they may be part of EGF receptor-mediated cellular signaling cascade. In vitro binding studies indicate that SH3 domains of Grb2 or RasGAP are required for their binding to huntingtin. Our results suggest that huntingtin may be a unique adapter protein for EGF receptor-mediated signaling and may be involved in the regulation of Ras-dependent signaling pathways.
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Center for Neurological Disease, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02114, USA.
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D048868:Adaptor Proteins, Signal Transducing; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D020690:GTPase-Activating Proteins; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020703:ras GTPase-Activating Proteins; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020690:GTPase-Activating Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases