The molecular basis by which transforming growth factor (TGF)-1 protects certain tumor cells from tumor necrosis factor (TNF) cytotoxicity was investigated. When pretreated with TGF-1, -2, and -3, murine L929S fibroblasts developed resistance to TNF cytotoxicity. Time course experiments revealed that TGF-1 initially induced both cellular protein-tyrosine phosphorylation and simultaneous secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein(s), which closely preceded the acquisition of TNF-resistance. TGF-2 and -3 also increased tyrosine phosphorylation. However, both molecules failed to stimulate TRT secretion. The increased levels of phosphorylation, particularly to 9 specific protein tyrosine kinase inhibitor-sensitive cellular proteins, appeared to alter the TNF killing pathway. TGF-1-induced TRT secretion required participation of unknown serum factors. TRT adhered strongly to polystyrene plates and resisted treatment with heat (60 °C, 30 min), collagenase, -macroglobulin, heparin, antibodies against TGF-s, and limited trypsin digestion. Notably, TRT promoted TNF-resistance via activation of tyrosine and serine/threonine kinase functions in L929S. Thus, the molecular pathway involves TGF-1-mediated initiation of a rapid tyrosine phosphorylation of cellular protein substrates (which alters TNF cytotoxic pathway), and a simultaneous secretion of TRT, which in turn signals the cells to maintain the levels of phosphorylation, thereby sustaining the TNF-resistance.

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