dorsal/arxiv
View SchemaSystems theory of Smad signaling
| Authors | D. C. Clarke, M. D. Betterton, X. Liu |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0603025 |
| URL | https://arxiv.org/abs/q-bio/0603025 |
| DOI | 10.1049/ip-syb:20050055 |
| Journal | IEE Proceedings - Systems Biology 153 (6), pp. 412-424 (2006) |
Abstract
Transforming Growth Factor-beta (TGF-beta) signalling is an important regulator of cellular growth and differentiation. The principal intracellular mediators of TGF-beta signalling are the Smad proteins, which upon TGF-beta stimulation accumulate in the nucleus and regulate transcription of target genes. To investigate the mechanisms of Smad nuclear accumulation, we developed a simple mathematical model of canonical Smad signalling. The model was built using both published data and our experimentally determined cellular Smad concentrations (isoforms 2, 3, and 4). We found in mink lung epithelial cells that Smad2 (8.5-12 x 10^4 molecules/cell) was present in similar amounts to Smad4 (9.3-12 x 10^4 molecules/cell), while both were in excess of Smad3 (1.1-2.0 x 10^4 molecules/cell). Variation of the model parameters and statistical analysis showed that Smad nuclear accumulation is most sensitive to parameters affecting the rates of RSmad phosphorylation and dephosphorylation and Smad complex formation/dissociation in the nucleus. Deleting Smad4 from the model revealed that rate-limiting phospho-R-Smad dephosphorylation could be an important mechanism for Smad nuclear accumulation. Furthermore, we observed that binding factors constitutively localised to the nucleus do not efficiently mediate Smad nuclear accumulation if dephosphorylation is rapid. We therefore conclude that an imbalance in the rates of R-Smad phosphorylation and dephosphorylation is likely an important mechanism of Smad nuclear accumulation during TGF-beta signalling.
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"abstract": "Transforming Growth Factor-beta (TGF-beta) signalling is an important\nregulator of cellular growth and differentiation. The principal intracellular\nmediators of TGF-beta signalling are the Smad proteins, which upon TGF-beta\nstimulation accumulate in the nucleus and regulate transcription of target\ngenes. To investigate the mechanisms of Smad nuclear accumulation, we developed\na simple mathematical model of canonical Smad signalling. The model was built\nusing both published data and our experimentally determined cellular Smad\nconcentrations (isoforms 2, 3, and 4). We found in mink lung epithelial cells\nthat Smad2 (8.5-12 x 10^4 molecules/cell) was present in similar amounts to\nSmad4 (9.3-12 x 10^4 molecules/cell), while both were in excess of Smad3\n(1.1-2.0 x 10^4 molecules/cell). Variation of the model parameters and\nstatistical analysis showed that Smad nuclear accumulation is most sensitive to\nparameters affecting the rates of RSmad phosphorylation and dephosphorylation\nand Smad complex formation/dissociation in the nucleus. Deleting Smad4 from the\nmodel revealed that rate-limiting phospho-R-Smad dephosphorylation could be an\nimportant mechanism for Smad nuclear accumulation. Furthermore, we observed\nthat binding factors constitutively localised to the nucleus do not efficiently\nmediate Smad nuclear accumulation if dephosphorylation is rapid. We therefore\nconclude that an imbalance in the rates of R-Smad phosphorylation and\ndephosphorylation is likely an important mechanism of Smad nuclear accumulation\nduring TGF-beta signalling.",
"arxiv_id": "q-bio/0603025",
"authors": [
"D. C. Clarke",
"M. D. Betterton",
"X. Liu"
],
"categories": [
"q-bio.MN",
"q-bio.SC"
],
"doi": "10.1049/ip-syb:20050055",
"journal_ref": "IEE Proceedings - Systems Biology 153 (6), pp. 412-424 (2006)",
"title": "Systems theory of Smad signaling",
"url": "https://arxiv.org/abs/q-bio/0603025"
},
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