2 DIFFERENT SIGNAL-TRANSDUCTION PATHWAYS CAN BE ACTIVATED BY TRANSFORMING GROWTH-FACTOR-BETA-1 IN EPITHELIAL-CELLS

Signal transduction initiated by transforming growth factor beta 1 (TG F beta 1) was studied in two sublines of the same colon carcinoma cell line, which respond in opposite ways to TGF beta 1, by proliferation or by growth inhibition. TGF beta 1 activates ras proteins within 5 mi n of addition when it acts to inhibit growth but not when it acts as a mitogen. In both cases TGF beta 1 also rapidly modulates the activiti es of three protein kinases, detected by their in gel kinase activity on the mitogen-activated protein kinase (MAP kinase) substrate, myelin basic protein (MBP), When TGF beta 1 acts as a mitogen for U9 cells, it increases the activity of MBP kinases of 57, 105, and 130 kDa withi n 10 min of the addition without detectably activating ras proteins. W hen TGF beta 1 inhibits the growth of HD3 cells, it activates ras prot eins and the 57-kDa MBP kinase within 5 min but inhibits the activity of the 105- and 130-kDa MBP kinases. In HD3 cells ras activation occur red in two signal transduction pathways, one from TGF beta 1 leading t o growth inhibition and one from epidermal growth factor (EGF) leading to proliferation. In addition to ras proteins, EGF activates a differ ent set of MBP kinases in HD3 cells than does TGF beta 1, MBP kinases of 85, 57, and 44 kDa. The latter is likely to be the 44-kDa MAP kinas e extracellular signal-regulated kinase (erk) 1, because EGF treatment of HD3 cells activates erk1 by increasing its phosphotyrosine level. Therefore, in two closely related epithelial cell lines TGF beta 1 act ivates two different signal transduction pathways, one ras-dependent a nd one ras-independent, and modulates the activities of a set of MBP k inases.