Differences in sensitivity of biological functions mediated by epidermal growth factor receptor activation with respect to endogenous and exogenous ligands.
Despite constitutive expression of autocrine transforming growth factor-alpha (TGF-alpha) in growth factor-independent colon carcinoma cells, the epidermal growth factor receptor (EGFr) is not saturated and can be further activated by exogenous EGFr ligand. Given that the activation of EGFr by exogenous growth factor has no further effect on DNA synthesis, the question arises as to what function this additional EGFr activation might have. We report that EGF induces integrin alpha2 expression, integrin-mediated adhesion, and micromotility of HCT116 cells. The stimulatory effect of ligand on these biological functions is abrogated by treatment with AG1478- and EGFr-blocking monoclonal antibody. This provides evidence that the biological responses are EGFr-mediated and EGFr is located upstream of integrin alpha2 expression. Therefore, although exogenous EGF has no effect on DNA synthesis beyond that induced by autocrine TGF-alpha (at subsaturating levels of EGFr occupation) exogenous growth factor does induce integrin alpha2 expression, cell adhesion, and micromotion. An important finding revealed by this study is the documentation of biological responses of EGFr-mediated functions, including DNA synthesis, cell adhesion, and micromotion, which differ in sensitivity with respect to different degrees of EGFr activation at the basal state and in response to exogenous ligand.
Sawhney
Rajinder S
RS
Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Zhou
Guo-Hao K
GH
Humphrey
Lisa E
LE
Ghosh
Paramita
P
Kreisberg
Jeffrey I
JI
Brattain
Michael G
MG
D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000502:physiology; D006801:Humans; D039421:Integrin alpha2; D008024:Ligands; D011799:Quinazolines; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D015703:Antigens, CD; D016326:Extracellular Matrix Proteins; D039421:Integrin alpha2; D008024:Ligands; D011799:Quinazolines; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors