The role of distinct p185neu extracellular subdomains for dimerization with the epidermal growth factor (EGF) receptor and EGF-mediated signaling

Proceedings of the National Academy of Sciences of the United States of America
Toru KumagaiM I Greene

Abstract

The extracellular domain of p185(c-neu) can be viewed as a complex structure of four subdomains, two of which are cysteine-rich subdomains. We have investigated the contribution of these distinct p185(c-neu) extracellular subdomains to p185/epidermal growth factor receptor (EGFR) heteromer formation and EGF-induced heteromeric signaling. Our studies indicate that at least two separate p185 subdomains, a region spanning subdomains I and II and subdomain IV are involved in association of p185 with the EGFR. We also demonstrated that subdomain IV reduced the heteromeric signaling and transforming activities induced by EGF after associating with EGFR. When 126 aa were deleted from subdomain IV, this small subdomain IV-derived fragment could still lead to heterodimers with EGFR and suppress EGF-induced mitogen-activated protein kinase activation and subsequent transformation abilities. These data provide information about trans-inhibitory mechanisms of mutant p185 species and also indicate that both the entire and a part of subdomain IV may represent a therapeutic target for erbB-overexpressing tumors. Finally, these studies define a basic feature of receptor-receptor associations that are determined by cystine-knot containing subdo...Continue Reading

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Citations

May 28, 2003·Protein Expression and Purification·Chao-Xing YuanRay Meade
Oct 21, 2003·Proceedings of the National Academy of Sciences of the United States of America·Jörg J JacobyXin-Yuan Fu
Jul 18, 2003·Proceedings of the National Academy of Sciences of the United States of America·Toru KumagaiMark I Greene
Jun 25, 2005·Experimental and Molecular Pathology·Qiang Wang, Mark I Greene
Sep 11, 2002·FEBS Letters·Jean DenaultRichard Leduc
Dec 28, 2018·International Journal of Molecular Sciences·Xiangfeng QinGuangfu Hu
May 16, 2002·The Journal of Biological Chemistry·Alan BerezovRamachandran Murali
Jan 5, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Keiji FuruuchiMark I Greene
Jun 5, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christel LarbouretDavid Azria

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