Mutation of one SLP76 tyrosine residue (Y145), but not others (Y112/Y128), impairs platelet function and clotting in mice.

Two receptors that trigger platelet activation relay their signals via different residues on the same adaptor, according to Bezman et al. (page 1775).

In platelets, the SLP76 adaptor scaffolds a signaling complex that activates platelets via two receptors: the GPVI immunoreceptor and the αIIbβ3 integrin. Three tyrosines at the SLP76 amino end—Y145, Y112, and Y128—constitute a major part of the molecule's business end. SLP76 works best in platelets when all three are phosphorylated, and mutations at all three tyrosines block platelet activation. Bezman et al. now find that the tyrosines selectively transmit signals from one or the other receptor.

This partiality became evident when the group created mutant mice defective either in Y145 or in both Y112 and Y128. Platelets from the Y145 mutants did not spread, aggregate, or degranulate—effects mediated by GPVI signals. These defects were associated with an inability to recruit and activate the known downstream molecules PLCγ2 and Vav1. These defects were milder in platelets from the dual mutant, which bound to both PLCγ2 and Vav1, but these cells were less sticky and did not form stable clots—effects attributed to αIIbβ3.

In T cells, mutations in any of the three SLP76 tyrosines cause defective T cell receptor signaling. But T cells that express two forms of SLP76—one mutated at Y112/128 and the other at Y145—remain functional, suggesting that the mutant SLP76s team up to recruit all the necessary molecules. Bezman et al. did not observe such complementation in platelets, however. T cells, which have many more immunoreceptors than platelets, might form larger signaling complexes in which different mutants are more likely to meet up and rescue each other.