A sequence conserved between CD

CD5 and CD6 are related surface receptors that limit and promote T‐cell responses. Co‐stimulatory effects of CD6 depend on binding a cell surface ligand, CD166, and recruitment of the intracellular adaptor proteins GADS and SLP‐76 by C‐terminal phosphotyrosines. We have continued to identify interactions of CD5 and CD6 to understand their roles in T‐cell activation. In a screen to identify binding partners for peptides containing a cytoplasmic sequence, SDSDY conserved between CD5 and CD6, we identified ezrin radixin moesin (ERM) proteins, which link plasma membrane proteins to actin. Purified radixin FERM domain bound directly to CD5 and CD6 SDSDY peptides in a phosphorylation‐dependent manner (KD = 0·5‐2 μm) at 37°. In human T‐cell blasts, mutation of the CD6 SDSDY sequence enhanced CD69 expression in response to CD3 monoclonal antibody. In this proximal readout, interactions of the SDSDY sequence were dominant compared with the C‐terminal tyrosines of CD6. In contrast, in a more downstream readout, interleukin‐2 expression, in response to immobilized CD3 and CD6 monoclonal antibodies, the C‐terminal tyrosines were dominant. The data suggest that varying functional effects of CD6 and potentially CD5 depend on interactions of different cytoplasmic regions with the cytoskeleton and alter depending on the stimuli