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J. Biol. Chem., Vol. 280, Issue 29, 27383-27392, July 22, 2005

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Reorganization of ErbB Family and Cell Survival Signaling after Knock-down of ErbB2 in Colon Cancer Cells^*

Yi Peter Hu¶, Srinivas Venkateswarlu||, Natalia Sergina||, Gillian Howell, Patricia St. Clair||, Lisa E. Humphrey, Wenhui Li||, Jennie Hauser, Elizabeth Zborowska**, James K. V. Willson**, and Michael G. Brattain

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, the ^||Department of Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, the ^**Department of Medicine and Case Western Reserve University/Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, and the Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43699

The role of the ErbB family in supporting the malignant phenotype was characterized by stable transfection of a single chain antibody (ScFv5R) against ErbB2 containing a KDEL endoplasmic reticulum retention sequence into GEO human colon carcinoma cells. The antibody traps ErbB2 in the endoplasmic reticulum, thereby down-regulating cell surface ErbB2. The transfected cells showed inactivation of ErbB2 tyrosine phosphorylation and reduced heterodimerization of ErbB2 and ErbB3. This resulted in greater sensitivity to apoptosis induced by growth deprivation and delayed tumorigenicity in vivo. Furthermore, decreased heterodimerization of ErbB2 and ErbB3 led to a reorganization in ErbB function in transfected cells as heterodimerization between epidermal growth factor receptor (EGFR) and ErbB3 increased, whereas ErbB3 activation remained almost the same. Importantly, elimination of ErbB2 signaling resulted in an increase in EGFR expression and activation in transfected cells. Increased EGFR activation contributed to the sustained cell survival in transfected cells.

Received for publication, December 17, 2004 , and in revised form, April 25, 2005.

^* This work was supported by National Institute of Health Grants CA34432, CA54807, and CA16056. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Submitted in partial fulfillment of the requirements for a Ph.D. at the Medical College of Ohio.

To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-3044; Fax: 716-845-8857; E-mail: Michael.brattain{at}roswellpark.org.

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