Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2.
Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2.
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DOI：
10.1182/blood.v96.2.483.014k40_483_490
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发表时间：
2000-07
期刊：
影响因子：
20.3
通讯作者：
Sujatha P. Paul;L. Taylor;Eryn K. Stansbury;D. McVicar
中科院分区：
文献类型：
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作者：
Sujatha P. Paul;L. Taylor;Eryn K. Stansbury;D. McVicar
CD33是唾液酸结合受体家族的髓样特异性成员，在髓样祖细胞上高度表达，但在分化细胞中表达水平低得多。人CD33在其胞质结构域中具有两个酪氨酸残基（Y340和Y358）。当磷酸化时，这些酪氨酸可以作为磷酸酶SHP-1和/或SHP-2的停靠位点，使CD33能够作为抑制性受体发挥作用。在这里，我们表明，CD33是酪氨酸磷酸化的磷酸酶抑制剂，过钒酸盐的存在下，和招聘SHP-1和SHP-2。共表达研究表明，Src家族激酶Lck是有效的磷酸化Y340，但不是Y358，这表明这些残基可能在选择性募集衔接分子的功能，并具有不同的功能。对Y340和Y358的作用重叠但非冗余的进一步支持来自肽结合研究，该研究揭示了SHP-1和SHP-2对Y340的募集，但仅SHP-2对Y358的募集。使用SHP-1突变体的分析表明，CD33的Y340主要结合SHP-1的氨基Src同源性-2结构域。CD33作为抑制性受体发挥作用的潜力通过其下调U937中CD64诱导的钙动员的能力来证明。这种抑制对SHP-1的依赖性通过用显性负性SHP-1阻断CD33介导的作用来证明。这一结果表明，CD33是一种抑制性受体，并且SHP-1磷酸酶在介导CD33功能中具有重要作用。进一步的研究对于鉴定CD33在体内抑制的受体及其在髓系发育中的功能至关重要。（血。2000; 96：483 - 490）
CD33 is a myeloid specific member of the sialic acid-binding receptor family and is expressed highly on myeloid progenitor cells but at much lower levels in differentiated cells. Human CD33 has two tyrosine residues in its cytoplasmic domain (Y340 and Y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, SHP-1 and/or SHP-2, enabling CD33 to function as an inhibitory receptor. Here we demonstrate that CD33 is tyrosine phosphorylated in the presence of the phosphatase inhibitor, pervanadate, and recruits SHP-1 and SHP-2. Co-expression studies suggest that the Src-family kinase Lck is effective at phosphorylating Y340, but not Y358, suggesting that these residues may function in the selective recruitment of adapter molecules and have distinct functions. Further support for overlapping, but nonredundant, roles for Y340 and Y358 comes from peptide-binding studies that revealed the recruitment of both SHP-1 and SHP-2 to Y340 but only SHP-2 to Y358. Analysis using mutants of SHP-1 demonstrated that binding Y340 of CD33 was primarily to the amino Src homology-2 domain of SHP-1. The potential of CD33 to function as an inhibitory receptor was demonstrated by its ability to down-regulate CD64-induced calcium mobilization in U937. The dependence of this inhibition on SHP-1 was demonstrated by blocking CD33-mediated effects with dominant negative SHP-1. This result implies that CD33 is an inhibitory receptor and also that SHP-1 phosphatase has a significant role in mediating CD33 function. Further studies are essential to identify the receptor(s) that CD33 inhibits in vivo and its function in myeloid lineage development. (Blood. 2000;96:483-490)