| First Author | Poirier A | Year | 2024 |
| Journal | Sci Signal | Volume | 17 |
| Issue | 817 | Pages | eadg4422 |
| PubMed ID | 38166031 | Mgi Jnum | J:344224 |
| Mgi Id | MGI:7572660 | Doi | 10.1126/scisignal.adg4422 |
| Citation | Poirier A, et al. (2024) The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation. Sci Signal 17(817):eadg4422 |
| abstractText | Thousand-and-one-amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naive CD4(+) T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3(-/-) T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes. |
