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Regulation of Transforming Growth Factor-β Activation by Discrete Sequences of Thrombospondin 1
Open accessAbstract
Transforming growth factor-beta (TGF-beta) is a potent growth regulatory protein secreted by virtually all cells in a latent form. A major mechanism of regulating TGF-beta activity occurs through factors that control the processing of the latent to the biologically active form of the molecule. We have shown previously that thrombospondin 1 (TSP1), a platelet alpha-granule and extracellular matrix protein, activates latent TGF-beta via a protease- and cell-independent mechanism and have localized the TGF-beta binding/activation region to the type 1 repeats of platelet TSP1. We now report that recombinant human TSP1, but not recombinant mouse TSP2, activates latent TGF-beta. Activation was further localized to the unique sequence RFK found between the first and the second type 1 repeats of TSP1 (amino acids 412-415) by the use of synthetic peptides. A peptide with the corresponding sequence in TSP2, RIR, was inactive. In addition, a hexapeptide GGWSHW, based on a sequence present in the type 1 repeats of both TSP1 and TSP2, inhibited the activation of latent TGF-beta by TSP1. This peptide bound to 125I-active TGF-beta and inhibited interactions of TSP1 with latent TGF-beta. TSP2 also inhibited activation of latent TGF-beta by TSP1, presumably by competitively binding to TGF-beta through the WSHW sequence. These studies show that activation of latent TGF-beta is mediated by two sequences present in the type 1 repeats of TSP1, a sequence (GGWSHW) that binds active TGF-beta and potentially orients the TSP molecule and a second sequence (RFK) that activates latent TGF-beta. Peptides based on these sites have potential therapeutic applications for modulation of TGF-beta activation.
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Citations
Cited by
Munger, J. S., Huang, X., Kawakatsu, H., Griffiths, M. J. D., Dalton, S. L., Wu, J., Pittet, J.-F., Kaminski, N., Garat, C., Matthay, M. A., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80545-0 · Cited by 2,076
REGULATION OF IMMUNE RESPONSES BY TGF-β
Letterio, J. J., & Roberts, A. B. (1998) · Annual Review of Immunology · doi:10.1146/annurev.immunol.16.1.137 · Cited by 1,890
TGF-β Activation and Function in Immunity
Travis, M. A., & Sheppard, D. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120257 · Cited by 856
Activation of latent TGF-β by thrombospondin-1: mechanisms and physiology
Murphy-Ullrich, J. E., & Poczatek, M. (2000) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(99)00029-5 · Cited by 586
Self-citationThe functions of thrombospondin-1 and-2
Lawler, J. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00143-5 · Cited by 440
Metadata
- Authors
- Schultz-Cherry, S., Chen, H., Mosher, D. F., Misenheimer, T. M., Krutzsch, H. C., Roberts, D. D., & Murphy-Ullrich, J. E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-03
- Volume
- 270
- Issue
- 13
- Pages
- 7304-7310
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2022665089
- Cited by
- 424
- References
- 0
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- The paper
- Schultz-Cherry, S., Chen, H., Mosher, D. F., Misenheimer, T. M., Krutzsch, H. C., Roberts, D. D., & Murphy-Ullrich, J. E. (1995). Regulation of Transforming Growth Factor-β Activation by Discrete Sequences of Thrombospondin 1. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.270.13.7304
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
