Abstract
SHP-1 is a cytosolic tyrosine phosphatase implicated in down-regulation of B cell antigen receptor signaling. SHP-1 effects on the antigen receptor reflect its capacity to dephosphorylate this receptor as well as several inhibitory comodulators. In view of our observation that antigen receptor-induced CD19 tyrosine phosphorylation is constitutively increased in B cells from SHP-l-deficient motheaten mice, we investigated the possibility that CD19, a positive modulator of antigen receptor signaling, represents another substrate for SHP-1. However, analysis of CD19 coimmunoprecipitable tyrosine phosphatase activity in CD19 immunoprecipitates from SHP-1-deficient and wild-type B cells revealed that SHP-1 accounts for only a minor portion of CD19-associated tyrosine phosphatase activity. As CD19 tyrosine phosphorylation is modulated by the Lyn protein-tyrosine kinase, Lyn activity was evaluated in wild-type and motheaten B cells. The results revealed both Lyn as well as CD19-associated Lyn kinase activity to be constitutively and inducibly increased in SHP-1-deficient compared with wild-type B cells. The data also demonstrated SHP-1 to be associated with Lyn in stimulated but not in resting B cells and indicated this interaction to be mediated via Lyn binding to the SHP-1 N-terminal SH2 domain. These findings, together with cyanogen bromide cleavage data revealing that SHP-1 dephosphorylates the Lyn autophosphorylation site, identify Lyn deactivation/dephosphorylation as a likely mechanism whereby SHP-1 exerts its influence on CD19 tyrosine phosphorylation and, by extension, its inhibitory effect on B cell antigen receptor signaling.
Highlights
B cell responses to antigen stimulation are transduced intracellularly via the B cell antigen receptor (BCR),1 a multimeric
Transmission of BCR signals via this intracellular circuitry is further regulated by the integration of accessory signals from BCR comodulators [3] and is highly dependent on reversible protein-tyrosine phosphorylation mediated by the balanced activities of protein-tyrosine kinases (PTKs) and phosphatases (PTPs) [4, 5]
Among the myriad of proteins implicated in the regulation of BCR signaling, the cytosolic protein-tyrosine phosphatase (PTP) SHP-1 is distinguished by its predominant role as an inhibitor of BCR-driven activation events [5]
Summary
B cell responses to antigen stimulation are transduced intracellularly via the B cell antigen receptor (BCR),1 a multimeric. As well as data revealing CD19 to be associated with the Lyn protein-tyrosine kinase following BCR engagement [25, 26] and identifying a central role for Lyn in modifying CD19 effects on B cell survival [33, 34], we investigated the possibility that SHP-1 influence on CD19 tyrosine phosphorylation is mediated via the regulation of Lyn activity.
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