Hematopoietic Cell Phosphatase Is Recruited to CD22 following B Cell Antigen Receptor Ligation

Abstract

Hematopoietic cell phosphatase is a nonreceptor protein tyrosine phosphatase that is preferentially expressed in hematopoietic cell lineages. Motheaten mice, which are devoid of (functional) hematopoietic cell phosphatase, have severe disturbances in the regulation of B cell activation and differentiation. Because signals transduced via the B cell antigen receptor are known to guide these processes, we decided to analyze molecular interactions between the hematopoietic cell phosphatase and the B cell antigen receptor. Ligation of the B cell antigen receptor induces moderate tyrosine phosphorylation of hematopoietic cell phosphatase and the formation of a multi-molecular complex containing additional 68-70- and 135-kDa phosphoproteins. In resting B cells most of the hematopoietic cell phosphatase proteins reside in the cytosolic compartment, whereas after B cell antigen receptor cross-linking, a small fraction translocates toward the membrane where it specifically binds to the 135-kDa phosphoprotein. This 135-kDa glycoprotein was identified as CD22, a transmembrane associate of the B cell antigen receptor complex. Together these findings provide the first direct evidence that this cytoplasmic tyrosine phosphatase is involved in antigen receptor-mediated B cell activation, suggesting that in vivo B cell antigen receptor constituents or associated molecules may serve as substrate for its catalytic activity.

SLP‐76 is recruited to CD22 and dephosphorylated by SHP‐1, thereby regulating B cell receptor‐induced c‐Jun N‐terminal kinase activation

“…In B cells, SHP-1 is recruited to ITIM in CD22 [22,23], CD72 [27,28], and PIR-B [28], and dephosphorylates several signaling molecules, thus negatively regulating BCR-initiated signals. To further define the regulatory mechanisms exerted by SHP-1, we searched for novel substrates of SHP-1 in B cells.…”

“…Three of the tyrosine residues are located within immunoreceptor tyrosine-based inhibitory motifs (ITIM) [21]. Phosphorylated tyrosine residues within ITIM provide binding sites for SHP-1, thus negatively regulating BCRinitiated signals [22,23]. This model is supported by a surface phenotype characteristic for the activated B cells and by greater BCR-induced increases in [Ca 2+ ] i in CD22-deficient B cells [24,25].…”

Src Homology Region 2 (SH2) Domain-Containing Phosphatase-1 Dephosphorylates B Cell Linker Protein/SH2 Domain Leukocyte Protein of 65 kDa and Selectively Regulates c-Jun NH2-Terminal Kinase Activation in B Cells

“…SHP-1 is also implicated in negative regulation of BCR-induced calcium mobilization and in the threshold determination of negative selection (22). Furthermore, SHP-1 is known to be recruited to phosphorylated immunoreceptor tyrosine-based inhibitory motifs found in the cytoplasmic region of CD22 (23,24) or CD72 (25,26), negatively regulating BCR signaling. However, precise biochemical mechanisms by which SHP-1 regulates downstream signaling pathways have been largely unknown.…”

“…SHP-1 has been implicated in negative regulation of the resting BCR complex (21) and in the threshold determination for BCR signaling and negative selection (22). Biochemical studies have demonstrated that SHP-1 is recruited to tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory motifs present in the cytoplasmic regions of CD22 (23,24) and CD72 (25,26), thus negatively regulating BCR-initiating signals. In addition, we have previously demonstrated that SHP-1 is constitutively associated with SLP-76 in the mouse immature B cell line, WEHI-231 (27).…”

CD19 Signaling Pathways Play a Major Role for Murine AIDS Induction and Progression

“…Following BCR cross-linking, the Src homology protein 1 tyrosine phosphatase associates with tyrosinephosphorylated CD22, which induces Src homology protein 1 phosphatase activity (22)(23)(24). This results in suppression of mitogen-activated protein kinase activation and counterregulation of CD19 effects (25).…”