Inhibition of a naturally occurring EGFR oncoprotein by the p185neu ectodomain: implications for subdomain contributions to receptor assembly

Oncogene
Donald M O'RourkeM I Greene

Abstract

Mutant Epidermal Growth Factor Receptor (EGFR) oncoproteins lacking most of subdomains I and II of the extracellular region, a deletion which includes most of the first of two cysteine-rich sequences, have been observed in multiple human epithelial tumors, including malignant gliomas. These EGFR oncoproteins, designated deltaEGFR or EGFRvIII, confer increased tumorigenicity in vivo and are often coexpressed with full-length EGFR in human tumors. We have expressed an ectodomain-derived, carboxyl-terminal deletion mutant of the p185neu oncogene (T691stop) in human glioblastoma cells coexpressing endogenous EGFR and activated deltaEGFR oncoproteins. The p185neu ectodomain-derived mutant forms heterodimers with deltaEGFR proteins and reduces the phosphotyrosine content and kinase activity of deltaEGFR monomers. As a consequence of T691stop neu expression and surface localization, cell proliferation in conditions of full growth and reduced serum and anchorage-independent growth in soft agar was reduced in glioblastoma cells expressing either endogenous EGFR alone or coexpressing EGFR and elevated levels of deltaEGFRs. T691stop neu mutant receptors abrogate the dramatic growth advantage conferred by deltaEGFR in vivo, suggesting that...Continue Reading

Citations

Jan 16, 2007·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Heping WangTing Lei
Dec 31, 2003·Molecular and Cellular Neurosciences·John A BoockvarDonald M O'Rourke
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Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Geng ZhangMark I Greene
Mar 21, 2007·Carcinogenesis·Michael V GrandalHans S Poulsen
May 24, 2003·Neurosurgery·Gurpreet S Kapoor, Donald M O'Rourke
Feb 18, 2010·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Reema ZeineldinLaurie G Hudson
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·B W ParkM I Greene
Sep 2, 1998·Proceedings of the National Academy of Sciences of the United States of America·D M O'RourkeM I Greene
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·T KumagaiM I Greene
Oct 2, 2012·Experimental and Molecular Pathology·E Aaron RunkleMark I Greene
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Sep 29, 2004·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Guido LammeringRupert K Schmidt-Ullrich
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