| First Author | Cattley RT | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 24 | Pages | 8236-8251 |
| PubMed ID | 32358062 | Mgi Jnum | J:297139 |
| Mgi Id | MGI:6453287 | Doi | 10.1074/jbc.RA120.012572 |
| Citation | Cattley RT, et al. (2020) Transforming growth factor beta (TGF-beta) receptor signaling regulates kinase networks and phosphatidylinositol metabolism during T-cell activation. J Biol Chem 295(24):8236-8251 |
| abstractText | The cytokine content in tissue microenvironments shapes the functional capacity of a T cell. This capacity depends on the integration of extracellular signaling through multiple receptors, including the T-cell receptor (TCR), co-receptors, and cytokine receptors. Transforming growth factor beta (TGF-beta) signals through its cognate receptor, TGFbetaR, to SMAD family member proteins and contributes to the generation of a transcriptional program that promotes regulatory T-cell differentiation. In addition to transcription, here we identified specific signaling networks that are regulated by TGFbetaR. Using an array of biochemical approaches, including immunoblotting, kinase assays, immunoprecipitation, and flow cytometry, we found that TGFbetaR signaling promotes the formation of a SMAD3/4-protein kinase A (PKA) complex that activates C-terminal Src kinase (CSK) and thereby down-regulates kinases involved in proximal TCR activation. Additionally, TGFbetaR signaling potentiated CSK phosphorylation of the P85 subunit in the P85-P110 phosphoinositide 3-kinase (PI3K) heterodimer, which reduced PI3K activity and down-regulated the activation of proteins that require phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) for their activation. Moreover, TGFbetaR-mediated disruption of the P85-P110 interaction enabled P85 binding to a lipid phosphatase, phosphatase and tensin homolog (PTEN), aiding in the maintenance of PTEN abundance and thereby promoting elevated PtdIns(4,5)P2 levels in response to TGFbetaR signaling. Taken together, these results highlight that TGF-beta influences the trajectory of early T-cell activation by altering PI3K activity and PtdIns levels. |
