scholarly journals Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-γ2 to Ras in B Cell Receptor Signaling

2003 ◽  
Vol 198 (12) ◽  
pp. 1841-1851 ◽  
Author(s):  
Masatsugu Oh-hora ◽  
Sachiko Johmura ◽  
Ari Hashimoto ◽  
Masaki Hikida ◽  
Tomohiro Kurosaki
Keyword(s):  
B Cell ◽  
Phospholipase C ◽  
Growth Factor Receptor ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Ras Activation ◽  
Attached Form

Two important Ras guanine nucleotide exchange factors, Son of sevenless (Sos) and Ras guanine nucleotide releasing protein (RasGRP), have been implicated in controlling Ras activation when cell surface receptors are stimulated. To address the specificity or redundancy of these exchange factors, we have generated Sos1/Sos2 double- or RasGRP3-deficient B cell lines and determined their ability to mediate Ras activation upon B cell receptor (BCR) stimulation. The BCR requires RasGRP3; in contrast, epidermal growth factor receptor is dependent on Sos1 and Sos2. Furthermore, we show that BCR-induced recruitment of RasGRP3 to the membrane and the subsequent Ras activation are significantly attenuated in phospholipase C-γ2–deficient B cells. This defective Ras activation is suppressed by the expression of RasGRP3 as a membrane-attached form, suggesting that phospholipase C-γ2 regulates RasGRP3 localization and thereby Ras activation.

scholarly journals Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling

2019 ◽  
Vol 3 (15) ◽  
pp. 2286-2297
Author(s):  
Xiaoyu Jiang ◽  
Xiaoqing Lu ◽  
Yu Zhang ◽  
Leda Lacaria ◽  
Brett J. Schuchardt ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Synapse Formation ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Bcr Signaling ◽  
B Cell Receptor Signaling ◽  
Putative Binding Site

Abstract Human germinal center (GC)–associated lymphoma (HGAL) is an adaptor protein expressed in GC B cells. HGAL regulates cell motility and B-cell receptor (BCR) signaling, processes that are central for the successful completion of the GC reaction. Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. The HGAL YEN motif (amino acids 107-109) is similar to the phosphopeptide motif pYXN used as a binding site to the growth factor receptor–bound protein 2 (Grb2). We demonstrate by biochemical and molecular methodologies that HGAL directly interacts with Grb2. Concordantly, microscopy studies demonstrate HGAL-Grb2 colocalization in the membrane central supramolecular activation clusters (cSMAC) following BCR activation. Mutation of the HGAL putative binding site to Grb2 abrogates the interaction between these proteins. Further, this HGAL mutant localizes exclusively in the peripheral SMAC and decreases the rate and intensity of BCR accumulation in the cSMAC. Furthermore, we demonstrate that Grb2, HGAL, and Syk interact in the same complex, but Grb2 does not modulate the effects of HGAL on Syk kinase activity. Overall, the interplay between the HGAL and Grb2 regulates the magnitude of BCR signaling and synapse formation.

scholarly journals Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS

2016 ◽  
Vol 113 (29) ◽  
pp. 8218-8223 ◽  
Author(s):  
William Y. C. Huang ◽  
Qingrong Yan ◽  
Wan-Chen Lin ◽  
Jean K. Chung ◽  
Scott D. Hansen ◽  
...  
Keyword(s):  
Single Molecule ◽  
Dwell Time ◽  
Growth Factor Receptor ◽  
Cell Receptor ◽  
Nucleotide Exchange ◽  
Fast Kinetics ◽  
Surface Receptors ◽  
Signaling Systems ◽  
Downstream Signaling ◽  
Son Of Sevenless

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.

scholarly journals Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation

2004 ◽  
Vol 101 (47) ◽  
pp. 16612-16617 ◽  
Author(s):  
Y. Aiba ◽  
M. Oh-hora ◽  
S. Kiyonaka ◽  
Y. Kimura ◽  
A. Hijikata ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Ras Activation

scholarly journals Mechanism of B-Cell Receptor-Induced Phosphorylation and Activation of Phospholipase C-γ2

2004 ◽  
Vol 24 (22) ◽  
pp. 9986-9999 ◽  
Author(s):  
Yeun Ju Kim ◽  
Fujio Sekiya ◽  
Benoit Poulin ◽  
Yun Soo Bae ◽  
Sue Goo Rhee
Keyword(s):  
B Cell ◽  
Phospholipase C ◽  
Lipase Activity ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Phosphorylation Sites ◽  
Jurkat T Cells ◽  
Tyrosine Residues ◽  
B Cell Signaling ◽  
Stimulation Of

ABSTRACT Phospholipase C-γ2 (PLC-γ2) plays an important role in B-cell signaling. Phosphorylation of various tyrosine residues of PLC-γ2 has been implicated in regulation of its lipase activity. With the use of antibodies specific for each of the putative phosphorylation sites, we have now shown that PLC-γ2 is phosphorylated on Y753, Y759, and Y1217 in response to engagement of the B-cell receptor in Ramos cells, as well as in murine splenic B cells. In cells stimulated maximally via this receptor, the extent of phosphorylation of Y1217 was three times that of Y753 or of Y759. Stimulation of Jurkat T cells or platelets via their immunoreceptors also elicited phosphorylation of Y753 and Y759 but not that of Y1217. A basal level of phosphorylation of Y753 was apparent in unstimulated lymphocytes. The extent of phosphorylation of Y753 and Y759, but not that of Y1217, correlated with the lipase activity of PLC-γ2. Examination of the effects of various pharmacological inhibitors and of RNA interference in Ramos cells suggested that Btk is largely, but not completely, responsible for phosphorylation of Y753 and Y759, whereas phosphorylation of Y1217 is independent of Btk. Finally, phosphorylation of Y1217 and that of Y753 and Y759 occurred on different PLC-γ2 molecules.

scholarly journals The autoinhibitory C-terminal SH2 domain of phospholipase C- 2 stabilizes B cell receptor signalosome assembly

2014 ◽  
Vol 7 (343) ◽  
pp. ra89-ra89 ◽  
Author(s):  
J. Wang ◽  
H. Sohn ◽  
G. Sun ◽  
J. D. Milner ◽  
S. K. Pierce
Keyword(s):  
B Cell ◽  
Phospholipase C ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
B Cell Receptor

scholarly journals Cbl Suppresses B Cell Receptor–Mediated Phospholipase C (Plc)-γ2 Activation by Regulating B Cell Linker Protein–Plc-γ2 Binding

2000 ◽  
Vol 191 (4) ◽  
pp. 641-650 ◽  
Author(s):  
Tomoharu Yasuda ◽  
Akito Maeda ◽  
Mari Kurosaki ◽  
Tohru Tezuka ◽  
Katsunori Hironaka ◽  
...  
Keyword(s):  
B Cell ◽  
Phospholipase C ◽  
Tyrosine Phosphorylation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
B Cell Receptor ◽  
Sh2 Domains ◽  
Negative Role ◽  
Src Homology ◽  
Cbl Protein

Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-γ2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-γ2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-γ2 tyrosine phosphorylation through its binding to the PLC-γ2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-γ2 to BLNK and the subsequent PLC-γ2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-γ2 pathway by inhibiting the association of PLC-γ2 with BLNK.

scholarly journals Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation

Blood ◽  
2015 ◽  
Vol 126 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Ta-Ming Liu ◽  
Jennifer A. Woyach ◽  
Yiming Zhong ◽  
Arletta Lozanski ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
B Cell ◽  
Phospholipase C ◽  
Cell Receptor ◽  
Receptor Activation ◽  
B Cell Receptor ◽  
Key Points ◽  
Signaling Events

Key Points Hypermorphic PLCγ2 is independent of BTK activation. SYK or LYN inhibition antagonizes mutant PLCγ2-mediated signaling events.

scholarly journals The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3603-3612 ◽  
Author(s):  
Julia Hoellenriegel ◽  
Sarah A. Meadows ◽  
Mariela Sivina ◽  
William G. Wierda ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Surface Receptors ◽  
Therapeutic Development ◽  
And Migration ◽  
Phosphoinositide 3 Kinase

Abstract In lymphocytes, the phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor–induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development.

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