Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells.
Src homology 2-containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor-alpha (TNF-alpha) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF-alpha (5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNF-alpha activated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNF-alpha on thymidine incorporation and c-fos promoter activity. In addition, TNF-alpha attenuated vascular endothelial growth factor- and epidermal growth factor-induced extracellular signal-regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF-alpha. Taken together, our results suggested that TNF-alpha inhibited growth factor-mediated cell proliferation through SHP-1 activation.
Nakagami
Hironori
H
Department of Medical Biochemistry, Ehime University Medical School, Ehime, Japan.
Cui
Tai-Xing
TX
Iwai
Masaru
M
Shiuchi
Tetsuya
T
Takeda-Matsubara
Yuko
Y
Wu
Lan
L
Horiuchi
Masatsugu
M
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004815:Epidermal Growth Factor; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases