SHPS-1 (or SIRP)is a member of the immunoglobulin (Ig) superfamily abundantly expressed in neurons and other cell types. Within its cytoplasmic domain, it possesses at least two immunoreceptor tyrosine-based inhibitory motifs, which are targets for tyrosine phosphorylation and mediate the recruitment of SHP-2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase. Since other immunoreceptor tyrosinebased inhibitory motifs-containing receptors have critical roles in the negative regulation of hemopoietic cell functions, we wanted to examine the expression of SHPS-1 in cells of hematological lineages. By analyzing a panel of hemopoietic cell lines, evidence was provided that SHPS-1 is abundantly expressed in macrophages and, to a lesser extent, in myeloid cells. No expression was detected in T-cell or B-cell lines. Expression of SHPS-1 could also be documented in normal ex vivo peritoneal macrophages. Further studies showed that SHPS-1 was an efficient tyrosine phosphorylation substrate in macrophages. However, unlike in non-hemopoietic cells, tyrosine-phosphorylated SHPS-1 in macrophages associated primarily with SHP-1 and not SHP-2. Finally, our analyses allowed us to identify several isoforms of SHPS-1 in mouse cells. In part, this heterogeneity was due to differential glycosylation of SHPS-1. Additionally, it was caused by the production of at least two distinct shps-1 transcripts, coding for SHPS-1 polypeptides having different numbers of Ig-like domains in the extracellular region. Taken together, these findings indicate that SHPS-1 is likely to play a significant role in macrophages, at least partially as a consequence of its capacity to recruit SHP-1.Protein tyrosine phosphorylation is involved in a wide variety of cellular responses, including growth factor-induced proliferation and differentiation, G-protein-coupled receptor signal transduction, and antigen/Fc receptor signaling (reviewed in Ref. 1). As the mechanisms inducing protein tyrosine phosphorylation are becoming well understood, significant interest has been directed toward identifying the processes involved in their negative regulation. As a result, numerous protein-tyrosine phosphatases (PTPs) 1 have been identified (reviewed in Ref.2). In some cases such as the hemopoietic cell phosphatase SHP-1, PTPs have been shown to be potent inhibitors of cell signaling.Generally, there is little known about the modes of recruitment and activation of PTPs in physiological situations. Nonetheless, a significant advance in our comprehension of these processes was provided by the discovery that certain inhibitory receptors on hemopoietic cells, such as Fc␥RIIB and killer inhibitory receptors, contain within their cytoplasmic domain a motif capable of inhibiting receptor-mediated signal transduction (Refs. 3 and 4; reviewed in Ref.
5). This sequence, termed immunoreceptor tyrosine-based inhibitory motif (ITIM), is (V/ I/T)XYXX(V/L) (where V is valine, I is isoleucine, T is threonine, L is leucine, Y is tyrosine, and X is any residue). Phosp...
