Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein.
Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor on U937 cells results in rapid and TNF dose-dependent phosphorylation of a cytosolic protein with an apparent molecular mass of 26,000 kDa (p26) and an isoelectric point of 5.6. Half-maximal phosphorylation of p26 was achieved at concentrations of 1.8 ng/ml and was detectable within 20 s of TNF-alpha treatment. p26 is phosphorylated exclusively at serine residues. p26 phosphorylation occurs at 37 degrees C as well as at 14 degrees C, indicating that internalization of the TNF receptor is not required for serine kinase activation. Dephosphorylation of p26 starts 10 min after TNF-induced phosphorylation, suggesting a possible regulatory function of this cytosolic protein within the post-TNF receptor signaling system. p26 is also phosphorylated upon treatment with lymphotoxin. In contrast, both interferon-gamma and lipopolysaccharide fail to induce p26 phosphorylation. Whereas phosphorylated p26 was detected in the TNF-sensitive breast cancer cell line CRL1500, other TNF-responsive tumor cell lines investigated lacked enhanced phosphorylation of p26 in response to TNF, indicating that the 26-kDa phosphoprotein (pp26) may be a cell type-specific second messenger molecule involved in TNF signal transduction in some, but not all, target cells. p26 is also phosphorylated in a subclone of U937 (U937.C27) that responds to TNF-alpha with differentiation, yet is resistant to TNF-alpha-mediated growth inhibition. In contrast, p26 is not phosphorylated in another U937 derivative (U937.G3) that is resistant to both TNF-alpha-induced growth arrest and differentiation, suggesting that pp26 may play a role in the TNF signaling pathway linked to differentiation processes rather than to growth control.
Schütze
S
S
Clinical Research Group of the Max-Planck-Society, University of Göttingen, Federal Republic of Germany.
Scheurich
P
P
Pfizenmaier
K
K
Krönke
M
M
D001943:Breast Neoplasms; D002454:Cell Differentiation; D002455:Cell Division; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse; D008970:Molecular Weight; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012694:Serine / Q000031:analogs & derivatives*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D008070:Lipopolysaccharides; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; D012694:Serine; D007371:Interferon-gamma