Glycobiology Advance Access originally published online on February 9, 2005
Glycobiology 2005 15(7):667-676; doi:10.1093/glycob/cwi048
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Characterization of inhibitory signaling motifs of the natural killer cell receptor Siglec-7: attenuated recruitment of phosphatases by the receptor is attributed to two amino acids in the motifs
3 Glyco-chain Functions Laboratory, Supra-biomolecular System Group, Frontier Research System, Institute of Physical and Chemical Research (RIKEN), Wako-shi, Saitama 351-0198, Japan; and 4 CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 560-0082, Japan
1 To whom correspondence should be addressed; e-mail: yasua{at}postman.riken.go.jp
2 Present address: Department of Anatomy, University of California, San Francisco, 600 16th Street, San Francisco, CA 94143
Received on August 29, 2004; revised on January 8, 2005; accepted on February 2, 2005
Siglec-7 (p75/AIRM1) is an inhibitory receptor on human natural killer cells (NK cells) and monocytes. The cytoplasmic domain of Siglec-7 contains two signaling motifs: a membrane-proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) (Ile435-Gln-Tyr-Ala-Pro-Leu440) and a membrane-distal motif (Asn458-Glu-Tyr-Ser-Glu-Ile463). We report here that, upon pervanadate (PV) treatment, Siglec-7 recruited the protein tyrosine phosphatases Src homology-2 (SH2) domain-containing protein-tyrosine phosphatase-1 (SHP-1) and SHP-2 less efficiently than did other inhibitory receptors such as Siglec-9 and leukocyte-associated Ig-like receptor (LAIR-1). Alignment of the amino acid sequences of the two Siglecs revealed only three amino acids difference in these motifs. To identify the amino acid(s) critical to recruitment efficiency, we prepared a series of Siglec-7-based mutants in which each of the three amino acids were replaced with the corresponding one of Siglec-9 (I435L, P439S, and N458T mutants). P439S and N458T mutants showed pronounced enhancement of SHP recruitment, but I435L mutant had little effect. A double mutant (P439S, N458T) or triple mutant (I435L, P439S, N458T) recruited SHPs as much as did Siglec-9, indicating that Pro439 in the proximal motif and Asn458 in the distal motif of Siglec-7 attenuate its ability to recruit phosphatases. These amino acids appeared to affect not only phosphatase recruitment but also the subsequent attenuation of Syk phosphorylation.
Key words: inhibitory motif / mutational analysis / Siglec / tyrosine phosphatase
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