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Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Abstract:
Signal transduction initiated by transforming growth factor beta 1 (TGF 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 min 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 activities 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 within 10 min of the addition without detectably activating ras proteins. When TGF beta 1 inhibits the growth of HD3 cells, it activates ras proteins 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 occurred in two signal transduction pathways, one from TGF beta 1 leading to growth inhibition and one from epidermal growth factor (EGF) leading to proliferation. In addition to ras proteins, EGF activates a different 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 kinase 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 activates two different signal transduction pathways, one ras-dependent and one ras-independent, and modulates the activities of a set of MBP kinases.
Insights
Transforming growth factor beta 1 (TGF beta 1) triggers distinct signal pathways in colon cancer cells, influencing proliferation or growth inhibition via ras protein activation and modulating mitogen-activated protein kinase (MAP kinase) activities.
Area of Science:
- Cellular biology
- Molecular signaling pathways
- Cancer research
Background:
- Transforming growth factor beta 1 (TGF beta 1) elicits varied cellular responses, including proliferation and growth inhibition.
- Understanding TGF beta 1's signal transduction is crucial for cancer therapy development.
Purpose of the Study:
- To investigate the distinct signal transduction pathways activated by TGF beta 1 in two colon carcinoma sublines with opposing responses.
- To elucidate the role of ras proteins and mitogen-activated protein kinase (MAP kinase) cascades in mediating TGF beta 1's effects.
Main Methods:
- Comparative analysis of signal transduction in U9 (proliferative) and HD3 (inhibitory) colon carcinoma cells.
- Assessment of ras protein activation and in-gel kinase activities of myelin basic protein (MBP) kinases following TGF beta 1 stimulation.
- Investigation of epidermal growth factor (EGF) signaling as a comparative pathway.
Main Results:
- TGF beta 1 activated ras proteins only when inhibiting growth in HD3 cells, not when promoting proliferation in U9 cells.
- TGF beta 1 modulated specific MBP kinase activities (57, 105, 130 kDa) differently depending on the cellular response (proliferation vs. inhibition).
- EGF activated distinct MBP kinases (85, 57, 44 kDa) in HD3 cells, with 44 kDa likely being extracellular signal-regulated kinase (erk) 1.
Conclusions:
- TGF beta 1 activates both ras-dependent and ras-independent signal transduction pathways in colon carcinoma cells.
- Differential modulation of MBP kinase activities contributes to the opposing cellular responses to TGF beta 1.
- Distinct signaling pathways activated by TGF beta 1 and EGF highlight complex cellular regulation in cancer.