Signal Processing in the TGF-beta Superfamily Ligand-receptor Network

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2006 Feb 1

PMID 16446785

Citations 59

Authors

Jose M G Vilar

Ronald Jansen

Chris Sander

Affiliations

Soon will be listed here.

Abstract

The TGF-beta pathway plays a central role in tissue homeostasis and morphogenesis. It transduces a variety of extracellular signals into intracellular transcriptional responses that control a plethora of cellular processes, including cell growth, apoptosis, and differentiation. We use computational modeling to show that coupling of signaling with receptor trafficking results in a highly versatile signal-processing unit, able to sense by itself absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This coupling controls whether the response of the receptor module is transient or permanent and whether or not different signaling channels behave independently of each other. Our computational approach unifies seemingly disparate experimental observations and suggests specific changes in receptor trafficking patterns that can lead to phenotypes that favor tumor progression.

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References

Vilar J, Guet C, Leibler S . Modeling network dynamics: the lac operon, a case study. J Cell Biol. 2003; 161(3):471-6. PMC: 2172934. DOI: 10.1083/jcb.200301125. View

Di Guglielmo G, Le Roy C, Goodfellow A, Wrana J . Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003; 5(5):410-21. DOI: 10.1038/ncb975. View

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

Kang Y, Siegel P, Shu W, Drobnjak M, Kakonen S, Cordon-Cardo C . A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003; 3(6):537-49. DOI: 10.1016/s1535-6108(03)00132-6. View

Goumans M, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C . Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell. 2003; 12(4):817-28. DOI: 10.1016/s1097-2765(03)00386-1. View

Thiery J . Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003; 15(6):740-6. DOI: 10.1016/j.ceb.2003.10.006. View

Siegel P, Massague J . Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003; 3(11):807-21. DOI: 10.1038/nrc1208. View

Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H . Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res. 2004; 566(1):9-20. DOI: 10.1016/s1383-5742(03)00033-4. View

Tan C, Brady A, Nickols H, Wang Q, Limbird L . Membrane trafficking of G protein-coupled receptors. Annu Rev Pharmacol Toxicol. 2004; 44:559-609. DOI: 10.1146/annurev.pharmtox.44.101802.121558. View

10.

de Caestecker M . The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev. 2004; 15(1):1-11. DOI: 10.1016/j.cytogfr.2003.10.004. View

11.

Mitchell H, Choudhury A, Pagano R, Leof E . Ligand-dependent and -independent transforming growth factor-beta receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol Biol Cell. 2004; 15(9):4166-78. PMC: 515349. DOI: 10.1091/mbc.e04-03-0245. View

12.

Monteleone G, Pallone F, Macdonald T . Smad7 in TGF-beta-mediated negative regulation of gut inflammation. Trends Immunol. 2004; 25(10):513-7. DOI: 10.1016/j.it.2004.07.008. View

13.

Stelling J, Sauer U, Szallasi Z, Doyle 3rd F, Doyle J . Robustness of cellular functions. Cell. 2004; 118(6):675-85. DOI: 10.1016/j.cell.2004.09.008. View

14.

Steiner M, Barrack E . Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol. 1992; 6(1):15-25. DOI: 10.1210/mend.6.1.1738367. View

15.

Yamashita H, Ten Dijke P, Franzen P, Miyazono K, Heldin C . Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem. 1994; 269(31):20172-8. View

16.

Sun P, Davies D . The cystine-knot growth-factor superfamily. Annu Rev Biophys Biomol Struct. 1995; 24:269-91. DOI: 10.1146/annurev.bb.24.060195.001413. View

17.

Cui W, Fowlis D, Bryson S, Duffie E, Ireland H, Balmain A . TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996; 86(4):531-42. DOI: 10.1016/s0092-8674(00)80127-0. View

18.

Bohm S, Grady E, Bunnett N . Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem J. 1997; 322 ( Pt 1):1-18. PMC: 1218151. DOI: 10.1042/bj3220001. View

19.

Massague J . TGF-beta signal transduction. Annu Rev Biochem. 1998; 67:753-91. DOI: 10.1146/annurev.biochem.67.1.753. View

20.

Worthylake R, Opresko L, Wiley H . ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999; 274(13):8865-74. DOI: 10.1074/jbc.274.13.8865. View