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Smad7 Binds to Smurf2 to Form an E3 Ubiquitin Ligase that Targets the TGFβ Receptor for Degradation

Kavsak, Peter, Rasmussen, Richele K., Causing, Carrie G., Bonni, Shirin, Zhu, Haitao, Thomsen, Gerald H., Wrana, Jeffrey L.·2000·Molecular Cell
DOI 10.1016/s1097-2765(00)00134-9
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Abstract

Ubiquitin-mediated proteolysis regulates the activity of diverse receptor systems. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. IFN gamma, which stimulates expression of Smad7, induces Smad7-Smurf2 complex formation and increases TGF beta receptor turnover, which is stabilized by blocking Smad7 or Smurf2 expression. Furthermore, Smad7 mutants that interfere with recruitment of Smurf2 to the receptors are compromised in their inhibitory activity. These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation.

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  • When ligand levels diminish, attenuators also diminish and receptors increase; signaling re-boot induces negative regulators, as observed for follistatin and follistatin-like, secondarily diminishing the intensity of age-elevated pathways.

    “When the levels of ligand(s) diminish, attenuators also diminish, and receptor(s) increase [62, 63]; signaling re-boot induces negative regulators, as we observed for follistatin and follistatin-like, secondarily diminishing the intensity of age-elevated pathways [64–66].”

    From Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin (2020) · cites this paper as [66]

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Research works printed but not linked: 35

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Metadata

Authors
Kavsak, P., Rasmussen, R. K., Causing, C. G., Bonni, S., Zhu, H., Thomsen, G. H., & Wrana, J. L.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2000-12
Volume
6
Issue
6
Pages
1365-1375
ISSN
1097-2765
DOI
10.1016/s1097-2765(00)00134-9
Cited by
1,205
References
0
Language
en
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