Reorganization of ErbB family and cell survival signaling after Knock-down of ErbB2 in colon cancer cells.
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.
Hu
Yi Peter
YP
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Venkateswarlu
Srinivas
S
Sergina
Natalia
N
Howell
Gillian
G
St Clair
Patricia
P
Humphrey
Lisa E
LE
Li
Wenhui
W
Hauser
Jennie
J
Zborowska
Elizabeth
E
Willson
James K V
JK
Brattain
Michael G
MG
D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology*; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000494:pharmacology; D018739:Oncogene Proteins v-erbB / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D004815:Epidermal Growth Factor; D007135:Immunoglobulin Variable Region; D018739:Oncogene Proteins v-erbB; D018719:Erb-b2 Receptor Tyrosine Kinases