F or any given receptor, there are mechanisms that regulate the activation of signal transduction pathways, as well as mechanisms that extinguish those signaling pathways. Responding to environmental signals requires that both positive and negative regulation proceed in an ordered manner. Much research has focused on lymphocyte antigen receptorinduced signal transduction pathways, and an understanding of some of the initial events has been gained. The mechanisms that terminate signaling are equally important but less well understood. The inability to properly extinguish activation cascades may result in inappropriate responses and perhaps even cell death. Concerning lymphocyte antigen receptors, antigen recognition results in the activation of intracellular protein tyrosine kinases, particularly members of the Src family kinases, as well as the ZAP-70/syk kinases. The key to antigeninduced signal transduction is the phosphorylation of critical tyrosines within the cytoplasmic domains of the TCR CD3/g" chain complex or the oe and 3 chains of the B cell antigen receptor (BCR)(1-3). The critical tyrosines are located within a characteristic sequence motif termed immunoreceptor tyrosine-based activation motif (ITAM). Inactivating antigen receptors requires dephosphorylation, yet the involved enzyme (s) or process (es) have not previously been identified. Several recent reports, including one in this issue, provide important information about the mechanisms of BCR inactivation (3a-6).

Potential insight into the negative regulation of immunoreceptors was gained by the discovery that the motheaten mice (me) harbor a mutation in the SHP gene (also known as PTP1C, HCP, SH-PTP1)(7, 8). The mutation renders me mice deficient in SHP protein. SHP is an SH2 domain containing protein tyrosine phosphatase (PTPase) and belongs to a subfamily that contains another mammalian member, syp (also known as PTP2C, PTP1D and SH-PTP2), and a Drosophila member, corkscrew (csw)(9-18). syp is thought to function in the positive regulation of receptor tyrosine kinases and to be the mammalian orthologue of csw. In contrast, the phenotype of the me mice suggests that SHP functions in the negative regulation of leukocyte activation, me mice have numerous immunological disorders, including chronic macrophage and neutrophil activation, lymphopenia, and circulating autoantibodies (19). The B lymphocyte populations are markedly disproportionate; there is an absence of CD5-B lymphocytes (B2 cells), while the CD5 § B lymphocytes (B1 cells) are present and increased in relative numbers in the spleen. The B1 lymphocytes are activated and produce