scholarly journals SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1449-1456 ◽  
Author(s):  
Deborah Jeannean Carver ◽  
Mohammad Javad Aman ◽  
Kodimangalam S. Ravichandran
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Membrane Localization ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Inositol Phosphatase ◽  
Membrane Bound ◽  
P70s6k Activation

Abstract Activation of the serine/threonine kinase Akt and the regulation of its activation are recognized as critical in controlling proliferative/survival signals via many hematopoietic receptors. In B lymphocytes, the B-cell receptor (BCR)-mediated activation of Akt is attenuated by co–cross-linking of BCR with the inhibitory receptor FcγRIIB1, and the binding of the SH2 domain-containing inositol phosphatase, SHIP, to FcγRIIB1. Because SHIP dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) and activation of Akt requires PIP3, the destruction of this phospholipid has been proposed as the mechanism for Akt inhibition. However, upstream kinases that activate Akt, such as PDK1, also require PIP3 for activation. In this report, we addressed whether SHIP inhibits Akt directly at the level of Akt recruitment to the membrane, indirectly through PDK recruitment/phosphorylation of Akt, or both. We generated stable B-cell lines expressing a regulatable, but constitutively membrane-bound Akt that still required PDK-dependent phosphorylation for activation. Several lines of evidence suggested that activation of this membrane-targeted Akt is not inhibited by FcγRIIB1/SHIP and that PDK is not a target for SHIP-mediated inhibition. These data demonstrate that SHIP inhibits Akt primarily through regulation of Akt membrane localization. We also observed during these studies that FcγRIIB1/SHIP does not inhibit p70S6k activation, even though several other PIP3-dependent events were down-regulated. Because the enhanced activation of Akt in the absence of SHIP correlates with hyperproliferation in the myeloid lineage, our data have implications for SHIP and Akt-dependent regulation of proliferation in the hematopoietic lineage.

scholarly journals SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1449-1456
Author(s):  
Deborah Jeannean Carver ◽  
Mohammad Javad Aman ◽  
Kodimangalam S. Ravichandran
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Membrane Localization ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Inositol Phosphatase ◽  
Membrane Bound ◽  
P70s6k Activation

Activation of the serine/threonine kinase Akt and the regulation of its activation are recognized as critical in controlling proliferative/survival signals via many hematopoietic receptors. In B lymphocytes, the B-cell receptor (BCR)-mediated activation of Akt is attenuated by co–cross-linking of BCR with the inhibitory receptor FcγRIIB1, and the binding of the SH2 domain-containing inositol phosphatase, SHIP, to FcγRIIB1. Because SHIP dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) and activation of Akt requires PIP3, the destruction of this phospholipid has been proposed as the mechanism for Akt inhibition. However, upstream kinases that activate Akt, such as PDK1, also require PIP3 for activation. In this report, we addressed whether SHIP inhibits Akt directly at the level of Akt recruitment to the membrane, indirectly through PDK recruitment/phosphorylation of Akt, or both. We generated stable B-cell lines expressing a regulatable, but constitutively membrane-bound Akt that still required PDK-dependent phosphorylation for activation. Several lines of evidence suggested that activation of this membrane-targeted Akt is not inhibited by FcγRIIB1/SHIP and that PDK is not a target for SHIP-mediated inhibition. These data demonstrate that SHIP inhibits Akt primarily through regulation of Akt membrane localization. We also observed during these studies that FcγRIIB1/SHIP does not inhibit p70S6k activation, even though several other PIP3-dependent events were down-regulated. Because the enhanced activation of Akt in the absence of SHIP correlates with hyperproliferation in the myeloid lineage, our data have implications for SHIP and Akt-dependent regulation of proliferation in the hematopoietic lineage.

GSK-3 Inhibitors in Regulation and Controlling of Colon Carcinoma

2021 ◽  
Vol 22 ◽  
Author(s):  
Sitansu Sekhar Nanda ◽  
Md Imran Hossain ◽  
Heongkyu Ju ◽  
Dong Kee Yi
Keyword(s):  
Colon Carcinoma ◽  
Clinical Studies ◽  
Glycogen Synthesis ◽  
Morphological Examination ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Adenocarcinoma Cells ◽  
Membrane Bound

Background: GSK-3 inhibitors became a novel therapeutic agent treating cancer. There are so many uses of GSK-3 inhibitor for treating cancer like breast cancer, lung cancer, gastric cancer, and no pathological changes are shown by the morphological examination of GSK-3. Objectives: This review describes the recent affairs using GSK-3 inhibitors, mainly treating in colon carcinoma. The authorsAuthors have also shown the different mechanisms of different GSK-3 inhibitors for treating various cancers and proposed some mechanisms that can be useful for further research by GSK-3 inhibitors for various cancerscancer including colon carcinoma. Results: The majority of the cancers and pre-cancerous lesions are stimulated by the transformation of membrane-bound arachidonic acid (AA) to eicosanoids for the viability, proliferation, and spread of cancer. GSK-3 inhibitors can reinstate hostility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) responsiveness in gastric adenocarcinoma cells. GSK-3, the final enzyme in glycogen synthesis, is a serine/threonine kinase that phosphorylates varied sequences that are more than a hundred in number, within proteins in an array of heterogeneous pathways. It is an essential module of an exceptionally huge number of cellular processes, a fundamental role in many metabolic processes and diseases. Many patients achieve long term remission with outstanding survival diagnosed with colon cancer through it. Conclusion: Before the extensive application of these proposed mechanisms of GSK-3 inhibitor, further evaluation and clinical studies are needed. After doing the appropriate clinical studies and morphological examination, it can be appropriate for extensive application.

The Pseudorabies Virus Serine/Threonine Kinase Us3 Contains Mitochondrial, Nuclear and Membrane Localization Signals

Virus Genes ◽  
2004 ◽  
Vol 29 (1) ◽  
pp. 131-145 ◽  
Author(s):  
Christine M. Calton ◽  
Jessica A. Randall ◽  
Melissa W. Adkins ◽  
Bruce W. Banfield
Keyword(s):  
Pseudorabies Virus ◽  
Membrane Localization ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

scholarly journals Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL

2010 ◽  
Vol 113 (2) ◽  
pp. 477-488 ◽  
Author(s):  
Yogita Kanan ◽  
Hiroyuki Matsumoto ◽  
Hongman Song ◽  
Maxim Sokolov ◽  
Robert E. Anderson ◽  
...  
Keyword(s):  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase

Involvement of PKCe in the Negative Regulation of Akt Activation Stimulated by G-CSF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2187-2187
Author(s):  
Hong Liu ◽  
Fan Dong
Keyword(s):  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Signaling Cascades ◽  
Granulocytic Differentiation ◽  
Serine Threonine Kinase ◽  
Akt Activation ◽  
Threonine Kinase ◽  
Receptor Mutant

Abstract Granulocyte colony-stimulating factor (G-CSF) supports the proliferation, differentiation and survival of myeloid cells by stimulating the activation of several signaling cascades including the serine/threonine kinase Akt pathway. Akt activation has been shown to be important for G-CSF-induced survival and granulocytic differentiation. Although significant progresses have been made in our understanding of the molecular mechanisms by which Akt is activated, much less is known about the signaling events that negatively regulate Akt activation. Interestingly, G-CSF-induced activation of Akt was completely inhibited when myeloid 32D cells transfected with the wild type G-CSF receptor were incubated with phorbol-12-myristate 13-acetate (PMA), a PKC activator. PMA-mediated inhibition of Akt activation occurred with 5 min and lasted at least 1 hour. Previously, it has been shown that a carboxyl terminally truncated G-CSF receptor (D715), whose expression is associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia (SCN), mediates significantly prolonged Akt activation. Notably, Akt activation by G-CSF in 32D cells expressing the D715 receptor mutant was rapidly downregulated by PMA treatment. The inhibitory effect of PMA on Akt activation was abolished by pretreatment of cells with the specific PKC inhibitor GF109203X, suggesting that PKC-dependent pathway negatively regulates Akt activation. Ro-31-7549, a specific inhibitor of PKCe, also abrogated PMA-mediated inhibition of Akt activation whereas rottlerin and Go6976, inhibitors of PKCd and PKC a/bI,, respectively, displayed no effect. Together, these results identified PKCe as being critically involved in PMA-mediated inhibition of Akt activation. Experiments are currently under way to determine the mechanism by which PKCe downregulates Akt activation and the role of PKCe in the regulation of cell proliferation, differentiation and survival in response to G-CSF.

The adaptor protein SH2D1A regulates signaling through CD150 (SLAM) in B cells

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4063-4070 ◽  
Author(s):  
Svitlana V. Mikhalap ◽  
Larysa M. Shlapatska ◽  
Olga V. Yurchenko ◽  
Maria Y. Yurchenko ◽  
Ganna G. Berdova ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
B Cell Differentiation ◽  
Akt Phosphorylation ◽  
Inositol Phosphatase ◽  
Extracellular Signal ◽  
Inositol Phosphatases

Abstract The CD150 receptor is expressed on activated T and B lymphocytes, dendritic cells, and monocytes. A TxYxxV/I motif in the CD150 cytoplasmic tail can bind different SH2-containing molecules, including tyrosine and inositol phosphatases, Src family kinases, and adaptor molecules. To analyze CD150-initiated signal transduction pathways, we used DT40 B-cell sublines deficient in these molecules. CD150 ligation on DT40 transfectants induced the extracellular signal-regulated kinase (ERK) pathway, which required SH2-containing inositol phosphatase (SHIP) but not SH2 domain protein 1A (SH2D1A). CD150-mediated Akt phosphorylation required Syk and SH2D1A, was negatively regulated by Lyn and Btk, but was SHIP independent. Lyn directly phosphorylated Y327 in CD150, but the Akt pathway did not depend on CD150 tyrosine phosphorylation and CD150-SHP-2 association. Analysis of CD150 and SH2D1A expression in non-Hodgkin and Hodgkin lymphomas revealed stages of B-cell differentiation where these molecules are expressed alone or coexpressed. Signaling studies in Hodgkin disease cell lines showed that CD150 is linked to the ERK and Akt pathways in neoplastic B cells. Our data support the hypothesis that CD150 and SH2D1A are coexpressed during a narrow window of B-cell maturation and SH2D1A may be involved in regulation of B-cell differentiation via switching of CD150-mediated signaling pathways. (Blood. 2004;104:4063-4070)

CD19 is essential for B cell activation by promoting B cell receptor–antigen microcluster formation in response to membrane-bound ligand

2007 ◽  
Vol 9 (1) ◽  
pp. 63-72 ◽  
Author(s):  
David Depoil ◽  
Sebastian Fleire ◽  
Bebhinn L Treanor ◽  
Michele Weber ◽  
Naomi E Harwood ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Activation ◽  
Membrane Bound

scholarly journals Distribution of the Src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells

1999 ◽  
Vol 342 (3) ◽  
pp. 697-705 ◽  
Author(s):  
Eric MURAILLE ◽  
Xavier PESESSE ◽  
Céline KUNTZ ◽  
Christophe ERNEUX
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
B Cell Activation ◽  
Mouse Tissues ◽  
Inhibitory Feedback ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Haemopoietic Cells

The termination of activation signals is a critical step in the control of the immune response; perturbation of inhibitory feedback pathways results in profound immune defects culminating in autoimmunity and overwhelming inflammation. FcγRIIB receptor is a well described inhibitory receptor. The ligation of B-cell receptor (BCR) and FcγRIIB leads to the inhibition of B-cell activation. Numerous studies have demonstrated that the SH2-domain-containing inositol 5-phosphatase SHIP (referred hereto as SHIP-1) is essential in this process. The cDNA encoding a second SH2-domain-containing inositol 5-phosphatase, SHIP-2, has been cloned [Pesesse, Deleu, De Smedt, Drayer and Erneux (1997) Biochem. Biophys. Res. Commun. 239, 697-700]. Here we report the distribution of SHIP-2 in mouse tissues: a Western blot analysis of mouse tissues reveals that SHIP-2 is expressed in both haemopoietic and non-haemopoietic cells. In addition to T-cell and B-cell lines, spleen, thymus and lung are shown to coexpress SHIP-1 and SHIP-2. Moreover, SHIP-2 is detected in fibroblasts, heart and different brain areas. SHIP-2 shows a maximal tyrosine phosphorylation and association to Shc after ligation of BCR to FcγRIIB but not after stimulation of BCR alone. Our results therefore suggest a possible role for SHIP-2 in the negative regulation of immunocompetent cells.

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