Leukocyte-associated Ig-like receptor-1 has SH2 domain-containing phosphatase-independent function and recruits C-terminal Src kinase.

Most inhibitory receptors in the immune system contain one or several immunoreceptor tyrosine-based inhibitory motifs (ITIM) and recruit the SH2 domain-containing phosphatases SHP-1, SHP-2 and/or SHIP, which are generally believed to be essential for the inhibitory function. However, it has not been systematically investigated whether ITIM-bearing receptors exert their function through alternative interactions. Here we describe that leukocyte-associated Ig-like receptor (LAIR)-1 has inhibitory function in DT40 chicken B cells that lack both SHP-1 and SHP-2. In addition, we found that LAIR-1 did not recruit SHIP upon phosphorylation. Thus, LAIR-1 can function independently from SH2 domain-containing phosphatases and must recruit at least one other signaling molecule. Using a yeast-tri-hybrid system, we found that phosphorylated LAIR-1 bound the C-terminal Src kinase (Csk). The interaction required the SH2 domain of Csk and phosphorylation of the tyrosine in the N-terminal ITIM of LAIR-1. We propose that Csk is an additional player in the regulation of the immune system by ITIM-bearing receptors.