SOCS-6 negatively regulates T cell activation through targeting p56 ^lck to proteasomal degradation

The T cell-specific tyrosine kinase, p56^lck, plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56 ^lck. SOCS-6 was identified as a protein binding to the kinase domain of p56^lck through yeast two-hybrid screening. SOCS-6 bound specifically to p56^lck (F505), which mimics the active form of p56^lck, but not to wild type p56^lck. In Jurkat Tcells, SOCS-6 binding to p56^lck was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56^lck. SOCS-6 promoted p56^lck ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.