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Positive and negative regulation of TGF-beta signaling
1Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), and Research for the Future Program, the Japan Society for the Promotion of Science, Toshima-ku, Tokyo 170-8455, Japan. miyazono-ind@umin.ac.jp.
Abstract:
Cytokines of the transforming growth factor beta (TGF-beta) superfamily, including TGF-betas, activins and bone morphogenetic proteins (BMPs), bind to specific serine/threonine kinase receptors and transmit intracellular signals through Smad proteins. Upon ligand stimulation, Smads move into the nucleus and function as components of transcription complexes. TGF-beta and BMP signaling is regulated positively and negatively through various mechanisms. Positive regulation amplifies signals to a level sufficient for biological activity. Negative regulation occurs at the extracellular, membrane, cytoplasmic and nuclear levels. TGF-beta and BMP signaling is often regulated through negative feedback mechanisms, which limit the magnitude of signals and terminate signaling. Negative regulation is also important for formation of gradients of morphogens, which is crucial in developmental processes. In addition, other signaling pathways regulate TGF-beta and BMP signaling through cross-talk. Nearly 20 BMP isoforms have been identified, and their activities are regulated by various extracellular antagonists. Regulation of TGF-beta signaling might be tightly linked to tumor progression, since TGF-beta is a potent growth inhibitor in most cell types.
Insights
Transforming growth factor beta (TGF-beta) superfamily cytokines, including TGF-betas and bone morphogenetic proteins (BMPs), signal via Smad proteins. Their activity is tightly regulated by positive and negative mechanisms, crucial for development and potentially linked to tumor progression.
Area of Science:
- Molecular Biology
- Cell Signaling
- Developmental Biology
Background:
- Cytokines in the TGF-beta superfamily, such as TGF-betas and BMPs, are crucial signaling molecules.
- These cytokines bind to serine/threonine kinase receptors, initiating intracellular signals mediated by Smad proteins.
- Smad proteins translocate to the nucleus to regulate gene transcription.
Purpose of the Study:
- To review the regulatory mechanisms of TGF-beta and BMP signaling pathways.
- To highlight the role of Smad proteins in signal transduction.
- To discuss the implications of TGF-beta signaling in tumor progression.
Main Methods:
- Literature review of TGF-beta and BMP signaling pathways.
- Analysis of Smad protein function in signal transmission.
- Examination of regulatory mechanisms at various cellular levels (extracellular, membrane, cytoplasmic, nuclear).
Main Results:
- TGF-beta and BMP signaling are modulated by both positive and negative regulatory mechanisms.
- Negative feedback loops are essential for limiting signal magnitude and terminating signaling.
- Negative regulation is critical for morphogen gradient formation during development.
- Cross-talk with other signaling pathways also influences TGF-beta and BMP signaling.
- Extracellular antagonists play a role in regulating the activity of numerous BMP isoforms.
Conclusions:
- TGF-beta and BMP signaling pathways are complex and tightly regulated.
- Negative regulation is vital for developmental processes and signal termination.
- Dysregulation of TGF-beta signaling may be closely associated with tumor progression due to its potent growth-inhibitory effects.