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J Mol Cell Biol. 2013 Dec;5(6):358-68. doi: 10.1093/jmcb/mjt017. Epub 2013 May 24.

Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells.

Author information

1
Department for Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria.

Abstract

T cell-intrinsic transforming growth factor β (TGFβ) receptor signaling plays an essential role in controlling immune responses. The RING-type E3 ligase Cbl-b has been shown to mediate the sensitivity of T cells to TGFβ; however, the mechanism underlying this process is unknown. This study shows that SMAD7, an established negative regulator of TGFβ receptor (TGFβR) signaling, is a key downstream effector target of Cbl-b. SMAD7 protein levels, but not SMAD7 mRNA levels, are upregulated in cblb(-/-) T cells. Cbl-b directly interacts with and ubiquitinates SMAD7, suggesting that Cbl-b posttranscriptionally regulates SMAD7. In support of this notion, concomitant genetic loss of SMAD7 in cblb(-/-) mice restored TGFβ sensitivity on T cell cytokine responses and abrogated the tumor rejection phenotype of cblb(-/-) mice. These results demonstrate an essential and non-redundant role for Cbl-b in controlling TGFβR signaling by directly targeting SMAD7 for degradation during T cell responses in vitro and in vivo.

KEYWORDS:

Cbl-b; SMAD; TGFβ signaling

PMID:
23709694
DOI:
10.1093/jmcb/mjt017
[Indexed for MEDLINE]

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