scholarly journals ITIM receptors: more than just inhibitors of platelet activation

Blood ◽  
2017 ◽  
Vol 129 (26) ◽  
pp. 3407-3418 ◽  
Author(s):  
Carmen H. Coxon ◽  
Mitchell J. Geer ◽  
Yotis A. Senis
Keyword(s):  
Platelet Activation ◽  
Platelet Reactivity ◽  
Protein Tyrosine Phosphatases ◽  
Negative Regulator ◽  
Src Homology 2 ◽  
Binding Partners ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Almost All ◽  
Activation Motif

Abstract Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. PECAM-1 was the first ITIM-containing receptor identified in platelets and appeared to conform to the established model of ITIM-mediated attenuation of ITAM-driven activation. PECAM-1 was therefore widely accepted as a major negative regulator of platelet activation and thrombosis for many years, but more recent findings suggest a more complex role for this receptor, including the facilitation of αIIbβ3-mediated platelet functions. Since the identification of PECAM-1, several other ITIM-containing platelet receptors have been discovered. These include G6b-B, a critical regulator of platelet reactivity and production, and the noncanonical ITIM-containing receptor TREM-like transcript-1, which is localized to α-granules in resting platelets, binds fibrinogen, and acts as a positive regulator of platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis. These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation.

The Src homology 2 domain–containing inositol 5-phosphatase negatively regulates Fcγ receptor–mediated phagocytosis through immunoreceptor tyrosine-based activation motif–bearing phagocytic receptors

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3374-3382 ◽  
Author(s):  
Koji Nakamura ◽  
Alexander Malykhin ◽  
K. Mark Coggeshall
Keyword(s):  
B Cells ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Dominant Negative ◽  
Src Homology 2 ◽  
Dominant Negative Form ◽  
Igg Receptors ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Activation Motif

Abstract Molecular mechanisms by which the Src homology 2 domain-containing inositol 5-phosphatase (SHIP) negatively regulates phagocytosis in macrophages are unclear. We addressed the issue using bone marrow–derived macrophages from FcγR- or SHIP-deficient mice. Phagocytic activities of macrophages from FcγRII(b)−/− and SHIP−/− mice were enhanced to a similar extent, relative to those from wild type. However, calcium influx was only marginally affected in FcγRII(b)−/−, but greatly enhanced in SHIP−/− macrophages. Furthermore, SHIP was phosphorylated on tyrosine residues upon FcγR aggregation even in macrophages from FcγRII(b)−/− mice or upon clustering of a chimeric receptor containing CD8 and the immunoreceptor tyrosine-based activation motif (ITAM)–bearing γ-chain or human-restricted FcγRIIa. These findings indicate that, unlike B cells, SHIP is efficiently phosphorylated in the absence of an immunoreceptor tyrosine-based inhibition motif (ITIM)–bearing receptor. We further demonstrate that SHIP directly bound to phosphorylated peptides derived from FcγRIIa with a high affinity, comparable to that of FcγRII(b). Lastly, FcγRIIa-mediated phagocytosis was significantly enhanced in THP-1 cells overexpressing dominant-negative form of SHIP in the absence of FcγRII(b). These results indicate that SHIP negatively regulates FcγR-mediated phagocytosis through all ITAM-containing IgG receptors using a molecular mechanism distinct from that in B cells.

scholarly journals The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2

2007 ◽  
Vol 407 (2) ◽  
pp. 255-266 ◽  
Author(s):  
Ian H. Batty ◽  
Jeroen van der Kaay ◽  
Alex Gray ◽  
Joan F. Telfer ◽  
Miles J. Dixon ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Specific Activity ◽  
Protein Tyrosine Phosphatases ◽  
Fold Increase ◽  
Inositol Polyphosphate ◽  
Src Homology 2 ◽  
Pi3k Activity ◽  
Src Homology ◽  
Src Homology 2 Domain

Activation of class Ia PI3K (phosphoinositide 3-kinase) produces PtdInsP3, a vital intracellular mediator whose degradation generates additional lipid signals. In the present study vanadate analogues that inhibit PTPs (protein tyrosine phosphatases) were used to probe the mechanisms which regulate the concentrations of these molecules allowing their independent or integrated function. In 1321N1 cells, which lack PtdInsP3 3-phosphatase activity, sodium vanadate or a cell permeable derivative, bpV(phen) [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V)], increased the recruitment into anti-phosphotyrosine immunoprecipitates of PI3K activity and of the p85 and p110α subunits of class Ia PI3K and enhanced the recruitment of PI3K activity stimulated by PDGF (platelet-derived growth factor). However, neither inhibitor much increased cellular PtdInsP3 concentrations, but both diminished dramatically the accumulation of PtdInsP3 stimulated by PDGF or insulin and markedly increased the control and stimulated concentrations of PtdIns(3,4)P2. These actions were accounted for by the ability of PTP inhibitors to stimulate the activity of endogenous PtdInsP3 5-phosphatase(s), particularly SHIP2 (Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2) and to inhibit types I and II PtdIns(3,4)P2 4-phosphatases. Thus bpV(phen) promoted the translocation of SHIP2 from the cytosol to a Triton X-100-insoluble fraction and induced a marked (5–10-fold) increase in SHIP2 specific activity mediated by enhanced tyrosine phosphorylation. The net effect of these inhibitors was, therefore, to switch the signal output of class I PI3K from PtdInsP3 to PtdIns(3,4)P2. A key component controlling this shift in the balance of lipid signals is the activation of SHIP2 by increased tyrosine phosphorylation, an effect observed in HeLa cells in response to both PTP inhibitors and epidermal growth factor.

scholarly journals Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes

2012 ◽  
Vol 447 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Ivan H. W. Ng ◽  
Dominic C. H. Ng ◽  
David A. Jans ◽  
Marie A. Bogoyevitch
Keyword(s):  
Nuclear Translocation ◽  
Gene Knockout ◽  
Transcriptome Profiling ◽  
Negative Regulator ◽  
Nuclear Retention ◽  
Physiological Importance ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Cytokine Stimulation

Phosphorylation of STAT3 (signal transducer and activator of transcription 3) is critical for its nuclear import and transcriptional activity. Although a shorter STAT3β spliceform was initially described as a negative regulator of STAT3α, gene knockout studies have revealed that both forms play critical roles. We have expressed STAT3α and STAT3β at comparable levels to facilitate a direct comparison of their functional effects, and have shown their different cytokine-stimulated kinetics of phosphorylation and nuclear translocation. Notably, the sustained nuclear translocation and phosphorylation of STAT3β following cytokine exposure contrasted with a transient nuclear translocation and phosphorylation of STAT3α. Importantly, co-expression of the spliceforms revealed that STAT3β enhanced and prolonged the phosphorylation and nuclear retention of STAT3α, but a STAT3β R609L mutant, with a disrupted SH2 (Src homology 2) domain, was not tyrosine phosphorylated following cytokine stimulation and could not cross-regulate STAT3α. The physiological importance of prolonged phosphorylation and nuclear retention was indicated by transcriptome profiling of STAT3−/− cells expressing either STAT3α or STAT3β, revealing the complexity of genes that are up- and down-regulated by the STAT3 spliceforms, including a distinct set of STAT3β-specific genes regulated under basal conditions and after cytokine stimulation. These results highlight STAT3β as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3α phosphorylation and nuclear retention after cytokine stimulation.

scholarly journals IL-6 blocks a discrete early step in lymphopoiesis

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 879-885 ◽  
Author(s):  
Kazuhiko Maeda ◽  
Yoshihiro Baba ◽  
Yoshinori Nagai ◽  
Kozo Miyazaki ◽  
Alexander Malykhin ◽  
...  
Keyword(s):  
Target Cells ◽  
Hematopoietic Progenitors ◽  
Early Step ◽  
Hematopoietic Stem ◽  
Lymphoid Lineage ◽  
Src Homology 2 ◽  
Multipotent Progenitors ◽  
Src Homology ◽  
Src Homology 2 Domain

Abstract Animals lacking Src homology 2 domain-containing inositol 5-phosphatase (SHIP) display a reduction in lymphopoiesis and a corresponding enhancement of myelopoiesis. These effects are mediated at least in part by elevated levels of interleukin 6 (IL-6). Here, we show the lymphopoiesis block in SHIP–/– mice is due to suppression of the lymphoid lineage choice by uncommitted progenitors. The suppression can be reproduced in vitro with recombinant IL-6, and IL-6 acts directly on hematopoietic progenitors. The block is partially overcome in SHIP–/– IL-6–/– double-deficient animals. IL-6 does not suppress but actually enhances proliferation of lymphoid-committed progenitors, indicating the IL-6 target cells are hematopoietic stem cells or multipotent progenitors. The findings suggest a mechanism for the lymphopenia that accompanies proinflammatory diseases.

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