Regulation of phospolipase C-γ2 and phosphoinositide 3-kinase by adaptor proteins in B cells

2001 ◽  
pp. 159-163
Author(s):  
Tomohiro Kurosaki
Keyword(s):  
B Cells ◽  
Adaptor Proteins ◽  
Phosphoinositide 3 Kinase

BCR activation of PI3K is Vav-independent in murine B cells

2004 ◽  
Vol 32 (5) ◽  
pp. 781-784 ◽  
Author(s):  
E. Vigorito ◽  
E. Clayton ◽  
M. Turner
Keyword(s):  
B Cells ◽  
Tyrosine Kinases ◽  
Adaptor Proteins ◽  
Pleckstrin Homology Domain ◽  
Pi3k Activation ◽  
Lipid Product ◽  
Lipid Kinases ◽  
Phosphoinositide 3 Kinase

BCR (B-cell antigen receptor)-induced Ca2+ signalling is initiated by activation of tyrosine kinases, which in concert with adaptor proteins and lipid kinases regulate PLC (phospholipase C) γ2 activation. Vav and PI3K (phosphoinositide 3-kinase) are required for optimal Ca2+ responses, although it has not been established, in primary B-cells, if both proteins are components of the same pathway. In vitro evidence suggests that binding of the PI3K lipid product PIP3 to Vav pleckstrin homology domain contributes to Vav activation. However, pharmacological inhibition of PI3K by wortmannin or deletion of the p110δ catalytic subunit has no effect on Vav activation in response to BCR engagement, suggesting that this mechanism does not operate in vivo. We also show that PI3K recruitment to phosphorylated-tyrosine-containing complexes is Vav-independent. Taken together with our previous observation that protein kinase B phosphorylation is normal in Vav-deficient B-cells, we suggest that PI3K activation is Vav-independent in response to strong signals delivered by multivalent cross-linking.

scholarly journals Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis

2011 ◽  
Vol 434 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Stephan Wullschleger ◽  
David H. Wasserman ◽  
Alex Gray ◽  
Kei Sakamoto ◽  
Dario R. Alessi
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signalling ◽  
Adaptor Proteins ◽  
Whole Body ◽  
Pleckstrin Homology Domain ◽  
Ph Domain ◽  
Enhanced Production ◽  
Pi3k Signalling ◽  
Inositol Phosphatases ◽  
Phosphoinositide 3 Kinase

Insulin sensitivity is critically dependent on the activity of PI3K (phosphoinositide 3-kinase) and generation of the PtdIns(3,4,5)P3 second messenger. PtdIns(3,4,5)P3 can be broken down to PtdIns(3,4)P2 through the action of the SHIPs (Src-homology-2-domain-containing inositol phosphatases). As PtdIns(3,4)P2 levels peak after those of PtdIns(3,4,5)P3, it has been proposed that PtdIns(3,4)P2 controls a negative-feedback loop that down-regulates the insulin and PI3K network. Previously, we identified two related adaptor proteins termed TAPP [tandem PH (pleckstrin homology)-domain-containing protein] 1 and TAPP2 that specifically bind to PtdIns(3,4)P2 through their C-terminal PH domain. To determine whether TAPP1 and TAPP2 play a role in regulating insulin sensitivity, we generated knock-in mice that express normal endogenous levels of mutant TAPP1 and TAPP2 that are incapable of binding PtdIns(3,4)P2. These homozygous TAPP1R211L/R211LTAPP2R218L/R218L double knock-in mice are viable and exhibit significantly enhanced activation of Akt, a key downstream mediator of insulin signalling. Consistent with increased PI3K and Akt activity, the double knock-in mice display enhanced whole body insulin sensitivity and disposal of glucose uptake into muscle tissues. We also generated wild-type and double TAPP1R211L/R211LTAPP2R218L/R218L knock-in embryonic fibroblasts and found that insulin triggered enhanced production of PtdIns(3,4,5)P3 and Akt activity in the double knock-in fibroblasts. These observations provide the first genetic evidence to support the notion that binding of TAPP1 and TAPP2 adap-tors to PtdIns(3,4)P2 function as negative regulators of the insulin and PI3K signalling pathways.

scholarly journals Essential Immunoregulatory Role for BCAP in B Cell Development and Function

2002 ◽  
Vol 195 (5) ◽  
pp. 535-545 ◽  
Author(s):  
Tetsuo Yamazaki ◽  
Kiyoshi Takeda ◽  
Kumiko Gotoh ◽  
Hiroshi Takeshima ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Phosphoinositide 3 Kinase ◽  
And Function ◽  
B Cell Deficiency

BCAP was recently cloned as a binding molecule to phosphoinositide 3-kinase (PI3K). To investigate the role of BCAP, mutant mice deficient in BCAP were generated. While BCAP-deficient mice are viable, they have decreased numbers of mature B cells and B1 B cell deficiency. The mice produce lower titers of serum immunoglobulin (Ig)M and IgG3, and mount attenuated responses to T cell–independent type II antigen. Upon B cell receptor cross-linking, BCAP-deficient B cells exhibit reduced Ca2+ mobilization and poor proliferative responses. These findings demonstrate that BCAP plays a pivotal immunoregulatory role in B cell development and humoral immune responses.

scholarly journals Tolerance of NK cells encountering their viral ligand during development

2008 ◽  
Vol 205 (8) ◽  
pp. 1819-1828 ◽  
Author(s):  
Joseph C. Sun ◽  
Lewis L. Lanier
Keyword(s):  
B Cells ◽  
Nk Cells ◽  
Adaptor Proteins ◽  
Interferon Γ ◽  
Target Cells ◽  
T And B Cells ◽  
Mcmv Infection ◽  
Retroviral Transduction ◽  
Activating Receptors ◽  
Activation Motif

During development, T and B cells encountering their cognate ligands via antigen-specific receptors are deleted or rendered anergic. Like T and B cells, natural killer (NK) cells express certain receptors, such as Ly49H, associated with immunoreceptor tyrosine-based activation motif–bearing adaptor proteins that transmit activating signals through Syk family kinases. Ly49H binds with high affinity to a mouse cytomegalovirus (MCMV)–encoded glycoprotein, m157, but does not recognize self-antigens. For comparison with the behavior of immature T and B cells exposed to foreign antigens, we addressed the fate of Ly49H+ NK cells that encountered their viral ligand during development by retroviral transduction of bone marrow stem cells with m157. In chimeric mice expressing m157, we observed a reduction in Ly49H+ NK cells in multiple tissues and less Ly49H on the cell surface. NK cells exposed to m157 during development appeared less mature, produced less interferon γ when stimulated through Ly49H, and were unable to kill m157-bearing target cells. After MCMV infection, these NK cells were severely impaired in their ability to proliferate. Thus, if immature NK cells encounter ligands for their activating receptors, regulatory mechanisms exist to keep these cells in an unresponsive state.

scholarly journals Daydreamer, a Ras effector and GSK-3 substrate, is important for directional sensing and cell motility

2013 ◽  
Vol 24 (2) ◽  
pp. 100-114 ◽  
Author(s):  
Verena Kölsch ◽  
Zhouxin Shen ◽  
Susan Lee ◽  
Katarzyna Plak ◽  
Pouya Lotfi ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Leading Edge ◽  
Adaptor Proteins ◽  
Cell Polarization ◽  
Glycogen Synthase Kinase 3 ◽  
Dynamic Regulation ◽  
Multiple Substrates ◽  
Directional Movement ◽  
Phosphoinositide 3 Kinase ◽  
Kinetics Of

How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA− cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA− cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA− cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.

Optimal B-cell proliferation requires phosphoinositide 3-kinase–dependent inactivation of FOXO transcription factors

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 784-787 ◽  
Author(s):  
Isharat Yusuf ◽  
Xiaocui Zhu ◽  
Michael G. Kharas ◽  
Jing Chen ◽  
David A. Fruman
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
B Cells ◽  
B Cell ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
Dependent Inactivation ◽  
Phosphoinositide 3 Kinase

AbstractTranscription factors of the Forkhead Box, class O (FOXO) family promote cell-cycle arrest and/or apoptosis in a variety of cell types. Mitogenic stimuli inactivate FOXO function by way of an evolutionarily conserved pathway involving the activation of phosphoinositide 3-kinase (PI3K) and its downstream effector, Akt. Although PI3K activation is required for B-lymphocyte proliferation, it is not known whether PI3K-dependent inactivation of FOXO proteins is important for cell-cycle progression and survival of these cells. Here, we show that B-cell receptor (BCR) engagement triggers PI3K-dependent phosphorylation and nuclear export of FOXO1. Furthermore, forced expression of PI3K-independent variants of FOXO1 or FOXO3a in activated B cells induces partial arrest in G1 phase of the cell cycle and increases apoptosis. These findings establish that FOXO inactivation is a functionally important consequence of PI3K signaling in primary B cells.

Bile acid secretion and direct targeting of mdr1-green fluorescent protein from Golgi to the canalicular membrane in polarized WIF-B cells

1999 ◽  
Vol 112 (24) ◽  
pp. 4535-4545
Author(s):  
Y. Sai ◽  
A.T. Nies ◽  
I.M. Arias
Keyword(s):  
Bile Acid ◽  
B Cells ◽  
Acid Secretion ◽  
Intracellular Trafficking ◽  
Fluorescent Protein ◽  
Canalicular Membrane ◽  
Canalicular Transporters ◽  
Phosphoinositide 3 Kinase ◽  
Green Fluorescent ◽  
Bile Acid Secretion

The bile canalicular membrane contains several ATP-dependent transporters that are involved in biliary secretion. Canalicular transporters are synthesized in ER, modified in Golgi and transported to the apical plasma membrane. However, the route and regulation of intracellular trafficking of ATP-dependent transporters have not been elucidated. In the present study, we generated a translational fusion of mdr1 and green fluorescent protein and investigated bile acid secretion and intracellular trafficking of mdr1 in WIF-B cells, a polarized liver derived cell line. Similar to hepatocytes, WIF-B cells secrete bile acids and organic cations (i.e. rhodamine-123) into the bile canaliculi. Canalicular secretion of fluorescein isothiocyanate-glycocholate was stimulated by taurocholate and a decapeptide activator of phosphoinositide 3-kinase and was decreased by wortmannin. WIF-B9 cells were transiently and stably transfected with a mdr1-GFP construct. Fluorescence was observed in the canalicular membrane, pericanalicular punctate structures and Golgi region. Time lapse microscopy revealed that mdr1-GFP is transferred from Golgi as tubular vesicular structures the majority of which traveled directly to the canalicular membrane. Recycling between the canalicular membrane and subapical region was also observed. At no time was mdr1-GFP detected in the basolateral plasma membrane. At 15 degrees C, mdr1-GFP accumulated in Golgi; after a shift to 37 degrees C, fluorescence moved directly to the canalicular membrane. This process was enhanced by taurocholate and blocked by wortmannin. In these studies as well, no mdr1-GFP fluorescence was observed at any time in basolateral membranes or other intracellular organelles. In conclusion, in WIF-B cells, there is a direct route from Golgi to the canalicular membrane for trafficking of mdr1, a bile canalicular ATP-dependent transporter of organic cations. As in normal hepatocytes, phosphoinositide 3-kinase regulates bile acid secretion and intracellular trafficking of mdr1 in WIF-B cells. WIF-B cells stably transfected with mdr1-GFP provide an important model in which to study trafficking and regulation of canalicular transporters. Movies available on-line: http://www.healthsci.tufts.edu/LABS/IMArias+++/Sai_F9.html

scholarly journals Insulin Receptor Substrate and p55 Orthologous Adaptor Proteins Function in theCaenorhabditis elegans daf-2/Insulin-like Signaling Pathway

2002 ◽  
Vol 277 (51) ◽  
pp. 49591-49597 ◽  
Author(s):  
Catherine A. Wolkow ◽  
Manuel J. Muñoz ◽  
Donald L. Riddle ◽  
Gary Ruvkun
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Sequence Similarity ◽  
Adaptor Proteins ◽  
Regulatory Subunit ◽  
Insulin Receptor Substrate ◽  
Genetic Screens ◽  
C Elegans ◽  
Insulin Receptor Substrates ◽  
Phosphoinositide 3 Kinase

An insulin-like signaling pathway regulates development and lifespan inCaenorhabditis elegans. Genetic screens that identified many components of theC. elegansinsulin pathway did not identify homologs of insulin receptor substrates or the phosphoinositide 3-kinase (PI3K) adaptor/regulatory subunit, which are both required for signaling by mammalian insulin/insulin-like growth factor I pathways. TheC. elegansgenome contains one homolog of each protein. TheC. elegansversions of insulin receptor substrate (IST-1) and PI3K p50/p55 (AAP-1) share moderate sequence similarity with their vertebrate andDrosophilacounterparts. Genetic experiments show thatist-1andaap-1potentiateC. elegansinsulin-like signaling, although they are not required for signaling in the pathway under most conditions. Worms lacking AAP-1 activity because of the mutationaap-1(m889) constitutively arrest development at the dauer larval stage when raised at high temperatures.aap-1mutants also live longer than wild-type animals, a phenotype observed in otherC. elegansmutants with defects in DAF-2 signaling. Interestingly, IST-1 appears to be required for signaling through a pathway that may act in parallel to AGE-1/PI3K.

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