Antigen receptor signaling: integration of protein tyrosine kinase functions

Tamir, Idan; Cambier, John C.

doi:10.1038/sj.onc.1202187

Cited by 106 publications

(89 citation statements)

References 110 publications

(140 reference statements)

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“…1 -generated signals activate Syk, Btk, and Src family protein tyrosine kinases during B lymphocyte activation (1)(2)(3)(4)(5). Kinase activation in turn propagates multiple downstream signaling events including tyrosine phosphorylation of important transmembrane receptors, phosphoinositide generation, increases in calcium mobilization into the cytoplasm, and the activation of mitogen-activated protein kinases (MAPKs).…”

Section: B Cell Antigen Receptor (Bcr)mentioning

confidence: 99%

CD22 Forms a Quaternary Complex with SHIP, Grb2, and Shc

Poe

Fujimoto

Jansen

et al. 2000

Journal of Biological Chemistry

116

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CD22 is a cell surface molecule that regulates signal transduction in B lymphocytes. Tyrosine-phosphorylated CD22 recruits numerous cytoplasmic effector molecules including SHP-1, a potent phosphotyrosine phosphatase that down-regulates B cell antigen receptor (BCR)-and CD19-generated signals. Paradoxically, B cells from CD22-deficient mice generate augmented intracellular calcium responses following BCR ligation, yet proliferation is decreased. To understand further the mechanisms through which CD22 regulates BCR-dependent calcium flux and proliferation, interactions between CD22 and effector molecules involved in these processes were assessed. The adapter proteins Grb2 and Shc were found to interact with distinct and specific regions of the CD22 cytoplasmic domain. Src homology-2 domain-containing inositol polyphosphate-5-phosphatase (SHIP) also bound phosphorylated CD22, but binding required an intact CD22 cytoplasmic domain. All three molecules were bound to CD22 when isolated from BCR-stimulated splenic B cells, indicating the formation of a CD22⅐Grb2⅐Shc⅐SHIP quaternary complex. Therefore, SHIP associating with CD22 may be important for SHIP recruitment to the cell surface where it negatively regulates calcium influx. Although augmented calcium responses in CD22-deficient mice should facilitate enhanced c-Jun N-terminal kinase (JNK) activation, BCR ligation did not induce JNK activation in CD22-deficient B cells. These data demonstrate that CD22 functions as a molecular "scaffold" that specifically coordinates the docking of multiple effector molecules, in addition to SHP-1, in a context necessary for BCR-dependent SHIP activity and JNK stimulation. B cell antigen receptor (BCR)1 -generated signals activate Syk, Btk, and Src family protein tyrosine kinases during B lymphocyte activation (1-5). Kinase activation in turn propagates multiple downstream signaling events including tyrosine phosphorylation of important transmembrane receptors, phosphoinositide generation, increases in calcium mobilization into the cytoplasm, and the activation of mitogen-activated protein kinases (MAPKs). Upon cell activation, MAPKs translocate to the nucleus and activate specific transcription factors (6 -9). Subfamilies of MAPKs include the extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38, which become fully activated as a result of dual phosphorylation on single threonine and tyrosine residues (reviewed in Ref. 10). BCR-induced calcium mobilization is essential for JNK, but not ERK or p38, activation (10 -12). Also critical to each of these events in B cells are cell surface receptors such as CD22 that modify and provide a context for BCR signal transduction (13).CD22 is a transmembrane glycoprotein that is expressed on the surface of mature B cells (14). The ϳ140-amino acid cytoplasmic domain of CD22 contains six tyrosines, some of which are rapidly phosphorylated following BCR or CD22 ligation (15, 16). These tyrosines are localized within immunoreceptor tyrosine-based inhibition motif...

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Section: B Cell Antigen Receptor (Bcr)mentioning

confidence: 99%

CD22 Forms a Quaternary Complex with SHIP, Grb2, and Shc

Poe

Fujimoto

Jansen

et al. 2000

Journal of Biological Chemistry

116

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“…This family includes only two members: Syk, which is present in most hematopoietic cells and ZAP-70, which is exclusively expressed in T and NK cells. As documented by several studies, the expression of Syk and ZAP-70 is essential for lymphocyte development and signal transduction via IRs (13)(14)(15)(16). The association of phosphorylated ITAMs with SH2 domains of Syk family PTKs leads to the activation of Syk and ZAP-70 mainly by autophosphorylation (17), thus allowing the propagation of IR signaling.…”

mentioning

confidence: 99%

Activation of Syk Tyrosine Kinase Is Required for c-Cbl-mediated Ubiquitination of FcεRI and Syk in RBL Cells

Paolini¹,

Molfetta²,

Beitz³

et al. 2002

Journal of Biological Chemistry

115

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Engagement of the high affinity receptor for IgE (Fc⑀RI) on mast cells and basophils results in Fc⑀RI ␤ and ␥ subunits ubiquitination by an as yet undefined mechanism. Here we show that, upon Fc⑀RI engagement on RBL-2H3 cells Syk undergoes ubiquitination and Syk kinase activity is required for its own ubiquitination and that of Fc⑀RI ␤ and ␥ chains. This requirement was demonstrated by overexpression of Syk wild-type or its kinase-dead mutant in RBL cells or using an Syk-deficient RBL-derived cell line transfected with wild-type or a kinase inactive form of Syk. We also identify c-Cbl as the E3 ligase responsible for both Syk and receptor ubiquitination. Furthermore, we demonstrate that Syk controls tyrosine phosphorylation of Syk-associated Cbl induced after receptor engagement. These data suggest a mutual regulation between Syk and Cbl activities. Finally, we show that a selective inhibitor of proteasome degradation induces persistence of tyrosine-phosphorylated receptor complexes, of activated Syk, and of Fc⑀RI-triggered degranulation. Our results provide a molecular mechanism for down-regulation of engaged receptor complexes by targeting ubiquitinated Fc⑀RI and activated Syk to the proteasome for degradation.The activation of protein-tyrosine kinases (PTKs) 1 is an essential event in the transduction of intracellular signals from immune receptors (IR), including the T and B cell antigen receptors (TCR and BCR, respectively), the high affinity receptor for IgE (Fc⑀RI), and the widely distributed receptors for IgG.These IRs contain multiple subunits: some, distinct for each receptor, are used for ligand binding, whereas others share conserved cytoplasmic motifs that are critical for the process of cell activation (immune receptor tyrosine-based activation motif, ITAM) (1-6). The IRs lack intrinsic kinase activity; however, within seconds of their engagement, PTKs are activated leading to phosphorylation of various substrates, including IR subunits (7-12). ITAM phosphorylation by the Src family PTKs provides docking sites for the tandem pair of Src homology 2 (SH2) domains of a second class of PTKs belonging to the Syk family (3-6). This family includes only two members: Syk, which is present in most hematopoietic cells and ZAP-70, which is exclusively expressed in T and NK cells. As documented by several studies, the expression of Syk and ZAP-70 is essential for lymphocyte development and signal transduction via IRs (13-16). The association of phosphorylated ITAMs with SH2 domains of Syk family PTKs leads to the activation of Syk and ZAP-70 mainly by autophosphorylation (17), thus allowing the propagation of IR signaling.We and others have demonstrated that Syk and ZAP-70 as well as IR subunits are subjected to an additional covalent modification following IR engagement in that they become modified by ubiquitin (Ub) (18 -22). Moreover, we have also provided evidence suggesting a direct correlation between IRinduced Syk and ZAP-70 ubiquitination and degradation (21).Ubiquitination, which consists in the covalen...

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“…The Src-family PTKs such as Lyn are located immediately downstream of BCR, and their activation is followed by the activation of two other PTKs, Syk and Btk (1)(2)(3)(4). It has been demonstrated that the activation of Btk depends, at least partially, on the activity of Lyn.…”

mentioning

confidence: 99%