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

Gruber T1, Hinterleitner R, Hermann-Kleiter N, Meisel M, Kleiter I, Wang CM, Viola A, Pfeifhofer-Obermair C, Baier G.
Source: J Mol Biol
Publication Date: (2013)
Issue: 5(6): 358-68
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Basic Research
Molecular Biology
Culture Media:
T cell-intrinsic transforming growth factor ß (TGFß) 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 TGFß; however, the mechanism underlying this process is unknown. This study shows that SMAD7, an established negative regulator of TGFß receptor (TGFßR) 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 TGFß 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 TGFßR signaling by directly targeting SMAD7 for degradation during T cell responses in vitro and in vivo.