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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 483-490
Myeloid specific human CD33 is an inhibitory receptor with
differential ITIM function in recruiting the phosphatases SHP-1 and
SHP-2
Sujatha P. Paul,
Lynn S. Taylor,
Eryn K. Stansbury, and
Daniel W. McVicar
From the Laboratory of Experimental Immunology, Division of Basic
Sciences, National Cancer Institute, NCI-FCRDC, Frederick, Maryland.
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.
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