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

Thomas Gruber, Reinhard Hinterleitner, Natascha Hermann-Kleiter, Marlies Meisel, Ingo Kleiter, Chiuhui Mary Wang, Antonella Viola, Christa Pfeifhofer-Obermair, Gottfried Baier

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)358-368
Number of pages11
JournalJournal of Molecular Cell Biology
Issue number6
Publication statusPublished - Dec 2013


  • Cbl-b
  • SMAD
  • TGFβ signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Genetics


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