Receptor biologists have traditionally focused on receptors that are physiologically coupled to inductive responses such as gene expression, cytokinesis, secretion, or entry into the cell cycle. It has generally been assumed that such inductive responses were terminated by ligand decay or receptor desensitization, which lead to cessation of signaling. While such mechanisms are clearly operative, a number of recent experiments have demonstrated that inhibitory receptors exist that function to attenuate inductive signals and further indicate that these receptors play a very important regulatory role in biology. Relatively few inhibitory receptors have been defined in part because the effects of these receptors can only be detected against the backdrop of an inductive signal. However, this situation is rapidly changing as recent pioneering studies have provided new approaches to isolation of such receptors. Three reports published in recent months (1–3), one by Kubagawa et al. in the Proceedings (1), have identified two new extended families of cell surface proteins that may function as inhibitory receptors. These findings are discussed below in the context of known inhibitory receptors and their mode of action (Table 1).

One of the first important insights regarding mechanisms of inhibitory signaling came from observations that signal transduction by tyrosine kinase-coupled receptors can be terminated by receptor association with phosphotyrosine phosphatases. A notable example is the termination of erythropoietin receptor signaling as a consequence of receptor phosphotyrosine binding to the hematopoietic lineage restricted phosphatase SHP-1 (previously known as HCP, SHPTP1, PTP1C, and SHP)(4). It was subsequently shown that FcRIIB, a receptor for immunoglobulin G constant (Fc) regions known to mediate inhibition of antigen receptor activation of B cells, could recruit SHP-1 as well as the closely related and ubiquitiously expressed phosphotyrosine phosphatase SHP-2 (previously known as SHPTP2, PTP1D, and Syp) to the receptor complex upon coligation with the antigen receptor (5, 6). SHP-1 expression was found to be necessary for FcRIIB inhibition of antigen receptor activation of B cell proliferation. Based in part on these findings, the role of these phosphatases in inhibitory signaling by CD22 (7), the newly described killer inhibitory receptors (KIRs)(8, 9), and CTLA4 (10) was explored. Activated receptors and/or phosphopeptides containing the cytoplasmic sequences of these molecules were found to bind SHP-1, SHP-2 or both phosphatases. More recently, Fujioka et al.(2) and subsequently Kharitonenkov et al.(3) isolated and cloned potential new inhibitory receptors based on their ability to coimmunoprecipitate with SHP-2. Fujioka et al.(2) isolated a protein they named SHP substrate 1 (SHPS-1) from v-src-transformed rat fibroblasts and subsequently cloned human and mouse SHPS-1 homologues. Using the same strategy Kharitonenkov et al.(3) isolated a family of proteins they named SIRPs (signal-regulatory proteins) of which SHPS-1 appears to be a member. SIRPs appear to be a broadly expressed multigene family with more than 15 members. SIRP1 was shown to be tyrosine phosphorylated fol-