Enhanced tumorigenesis of NR6 cells which express non-down-regulating epidermal growth factor receptors.
Sequences in the regulatory carboxyl terminus of the epidermal growth factor (EGF) receptor are required for ligand-induced internalization via a high-affinity saturable endocytic pathway and for receptor down-regulation. To investigate the role of down-regulation in attenuating mitogenic signals, we compared the ability of NR6 cells expressing holo and mutant down-regulation defective EGF receptors to form tumors in athymic mice. NR6 cells expressing mutant EGF receptors reproducibly formed rapidly growing tumors, whereas cells expressing holo EGF receptors had a low tumorigenic potential. Serial passage of tumors of NR6 cells expressing mutant EGF receptors resulted in an enhanced rate of tumor formation that directly correlated with increased expression of mutant receptors. Tumor growth was inhibited by a competitive antagonist anti-EGF receptor monoclonal antibody. Excessive signaling from the cell surface can result from lack of sequences required for endocytosis and from saturation of endocytic mechanisms. Non-down-regulating kinase-active EGF receptors provide an especially strong growth signal, manifested as rapid tumor growth in athymic mice.
Memorial Sloan Kettering Institute, New York, New York 10021.
H
H
Masui
A
A
Wells
C S
CS
Lazar
M G
MG
Rosenfeld
G N
GN
Gill
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D066246:ErbB Receptors / Q000032:analysis* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000209:etiology*
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors