B cell antigen receptor cross‐linking induces tyrosine phosphorylation and membrane translocation of a multimeric Shc complex that is augmented by CD19 co‐ligation

Lankester, Arjan C.; Schijndel, G. M. J. Van; Rood, P. M. L.; Verhoeven, Arthur J.; Lier, R. A. W. Van

doi:10.1002/eji.1830241136

Cited by 53 publications

(31 citation statements)

References 60 publications

(19 reference statements)

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“…On BCR activation, Shc is phosphorylated on tyrosine residues in a Lyn and Syk dependent manner and binds Grb2/Sos complexes (Saxton et al, 1994;Lankester et al, 1994;Smit et al, 1994). Interestingly, Shc also appears to associate with nonphosphorylated ITAM on the Ig-␣ chain of the resting BCR (D'Ambrosio et al, 1996), suggesting a mechanism for efficient recruitment of Shc to tyrosine phosphorylated ITAM following stimulation.…”

Section: Shc In Antigen Receptor Signalingmentioning

confidence: 99%

“…A role for Shc has been proposed in the integration of the signals triggered by the BCR and CD19. Coengagement of the BCR and CD19 has indeed been shown to enhance both the tyrosine phosphorylation of Shc and the formation of Shc/Grb2/Sos complexes, compared with ligation of the BCR alone (Lankester et al, 1994). Although the mechanism of Shc recruitment to CD19 has not been investigated, the physical and functional coupling of CD19 to Src family PTKs suggests that the latter might subserve this function.…”

Section: Integration Of Antigen Receptor and Coreceptor Signalsmentioning

confidence: 99%

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Lymphocyte Antigen Receptor Signal Integration and Regulation by the SHC Adaptor

Baldari

Telford²

1999

Biological Chemistry

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The Shc adaptor protein transduces signals from transmembrane receptors to the Ras pathway of cell activation by providing binding sites for the recruitment to the submembrane compartment of the Grb2/ Sos G-nucleotide exchange complex. The need for Shc in this process is however unclear since Grb2 can be recruited directly to phosphotyrosine containing membrane receptors through its src-homology-2 domain. Evidence from studies in lymphocytes indicates that Shc is multifunctional and is involved in the integration of independent signals to the Ras pathway. Furthermore, Shc may be a key control point at which signaling can be modulated both by interfering signals and by feedback mechanisms. Here we review recent literature to support these functions for Shc.

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Section: Shc In Antigen Receptor Signalingmentioning

confidence: 99%

Section: Integration Of Antigen Receptor and Coreceptor Signalsmentioning

confidence: 99%

Lymphocyte Antigen Receptor Signal Integration and Regulation by the SHC Adaptor

Baldari

Telford²

1999

Biological Chemistry

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“…In growth factor-stimulated cells, Sos translocation is mediated by the adapter proteins, Grb2 and Shc (11). BCR triggering causes the association of Sos with the adaptors Shc and Grb2 (12)(13)(14). The ternary complex of Shc, Grb2, and Sos is associated with the plasma membrane after BCR triggering, consistent with an essential role for the adapter proteins.…”

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confidence: 99%

Convergence of Signaling Pathways on the Activation of ERK in B Cells

Jacob

Cooney

Pradhan

et al. 2002

Journal of Biological Chemistry

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The B cell receptor (BCR) initiates three major signaling pathways: the Ras pathway, which leads to extracellular signal-regulated kinase (ERK) activation; the phospholipase C-␥ pathway, which causes calcium mobilization; and the phosphoinositide 3-kinase (PI 3-kinase) pathway. These combine to induce different biological responses depending on the context of the BCR signal. Both the Ras and PI 3-kinase pathways are important for B cell development and activation. Several model systems show evidence of cross-regulation between these pathways. Here we demonstrate through the use of PI 3-kinase inhibitors and a dominant-negative PI 3-kinase construct that the BCR-induced phosphorylation and activation of ERK is dependent on PI 3-kinase. PI 3-kinase feeds into the Ras signaling cascade at multiple points, both upstream and downstream of Ras. We also show that ERK activation is dependent on phospholipase C-␥, in keeping with its dependence on calcium mobilization. Last, the activation of PI 3-kinase itself is completely dependent on Ras. We conclude that the PI 3-kinase and Ras signaling cascades are intimately connected in B cells and that the activation of ERK is a signal integration point, since it requires simultaneous input from all three major signaling pathways. Triggering the B cell antigen receptor (BCR)1 by antigen or polyclonal activators initiates signaling cascades that lead to various cellular responses (1). Receptor ligation is followed by the phosphorylation of the immunoreceptor tyrosine-based activation motifs (2-4), which recruit cytosolic proteins and enzymes. Receptor recruitment brings enzymes into proximity of their substrates or kinases, which permits the sequential reactions that form the basis of signaling cascades. Three such cascades stimulated by immunoreceptors involve Ras, phosphoinositide 3-kinase (PI 3-kinase), and phospholipase C-␥ (PLC-␥) (reviewed in Ref. 1).The activation of PI 3-kinases results in the rapid accumulation of D-3 phosphorylated inositol phospholipids in the cell membrane (5). PI 3-kinase products bind with high specificity to pleckstrin homology domains of signaling proteins, to recruit pleckstrin homology domain-containing enzymes to the plasma membrane and promote their subsequent activation (6, 7). Class IA PI 3-kinases, the major class induced by tyrosine kinase-dependent receptors (6) consist of an SH2 domain-containing adapter p85 subunit that is constitutively bound to a catalytic p110 subunit. Animals lacking the p85 isoform p85␣ show a defect in B cell development, and mature B cells from these animals are impaired in their response to anti-IgM (8, 9). The activation of Ras requires the membrane localization of a guanine nucleotide exchange factor (GEF) such as Sos (10). In growth factor-stimulated cells, Sos translocation is mediated by the adapter proteins, Grb2 and Shc (11). BCR triggering causes the association of Sos with the adaptors . The ternary complex of Shc, Grb2, and Sos is associated with the plasma membrane after BCR triggering, consistent wi...

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“…Following ligation of the BCR the PTK, Lyn, tyrosine phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the accessory transducing molecules Ig-␣ (CD79a) and Ig-␤ (CD79b), leading to the recruitment and activation of additional PTKs (such as Syk, Lyn, Blk, and Fyn) and signaling molecules (PLC-␥ and RasGAP) and adaptors (Shc and Grb2) in an Src homology (SH)2-and SH3-domain-dependent manner (11). Thus, Shc binds to the phosphorylated ITAMs (12)(13)(14) and, in turn, is phosphorylated by Syk, permitting recruitment of the Grb2Sos complexes required for activation of Ras at the plasma membrane. Following Sos-driven guanine nucleotide exchange and generation of the GTP-bound form of Ras, Ras binds and derepresses Raf Ser/Thr kinase, triggering stimulation of MAP kinase kinase and consequent activation of ErkMAP kinase (11).…”

mentioning

confidence: 99%

A Filarial Nematode-Secreted Phosphorylcholine-Containing Glycoprotein Uncouples the B Cell Antigen Receptor from Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase by Promoting the Surface Ig-Mediated Recruitment of Src Homology 2 Domain-Containing Tyrosine Phosphatase-1 and Pac-1 Mitogen-Activated Kinase-Phosphatase

Deehan

Harnett

2001

The Journal of Immunology

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Unraveling the molecular mechanisms by which filarial nematodes, major human pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62), a homologue of phosphorylcholine-containing molecules that are secreted by human parasites and which is active in rodent models of filarial infection, is able to polyclonally activate certain protein tyrosine kinase and mitogen-activating protein kinase signal transduction elements in B lymphocytes. Such activation mediates desensitization of subsequent B cell Ag receptor (BCR) ligation-induced activation of extracellular signal-regulated kinase-mitogen-activated protein (ErkMAP) kinase and ultimately B cell proliferation. We now show that the desensitization is due to ES-62 targeting two major regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 primes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Igαβ-ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinase signaling in ES-62-primed B cells is terminated by the MAP kinase phosphatase, Pac-1 that is activated consequently to challenge via the BCR.

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B cell antigen receptor cross‐linking induces tyrosine phosphorylation and membrane translocation of a multimeric Shc complex that is augmented by CD19 co‐ligation

Cited by 53 publications

References 60 publications

Lymphocyte Antigen Receptor Signal Integration and Regulation by the SHC Adaptor

Lymphocyte Antigen Receptor Signal Integration and Regulation by the SHC Adaptor

Convergence of Signaling Pathways on the Activation of ERK in B Cells

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