Serine/Threonine Dephosphorylation May Be Involved in Tyrosine Phosphorylation: A New Mode of Signal Transduction in Platelets

Artçanuthurry, Valérie; Grelac, Françoise; Maclouf, Jacques; Martin-Cramer, Elisabeth; Lévy-Toledano, S

doi:10.1055/s-2007-999026

Cited by 11 publications

(10 citation statements)

References 35 publications

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“…First, how can inhibition of a Ser/Thr phosphatase (PP2Ac␣) activate a tyrosine kinase (Src)? While the occurrence of such a cross-talk has been widely accepted (24), the underpinning mechanisms are not clear. Inhibition of PP2Ac is likely to alter the Ser/Thr phosphorylation of multiple cellular proteins, including some that have the potential to regulate Src activity.…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Pradhan

Alrehani

Patel

et al. 2010

Journal of Biological Chemistry

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Stable platelet-platelet and platelet-extracellular matrix interactions play a critical role in hemostasis and thrombosis. These interactions can be mediated by integrin ␣ IIb ␤ 3 signaling at the sites of vascular injury. The binding of ␣ IIb ␤ 3 to an extracellular ligand-like fibrinogen triggers outside-in signals in platelets via modulation of the activities of several kinases and phosphatases. These signals in turn regulate the cytoskeletal reorganization, which contributes to stable platelet adhesion and spreading events (1). Signaling molecules, including the tyrosine kinase c-Src (2), protein tyrosine phosphatase 1 B (PTP-1B) 3 (3), and the catalytic subunit of protein phosphatase 2A (PP2Ac) (4) either associate constitutively or are recruited to the ␣ IIb ␤ 3 complex in response to integrin engagement. Kinases and phosphatases that assemble within the protein complexes organized by the cytoplasmic tails of ␣ IIb and ␤ 3 could facilitate reversible phosphorylation of multiple effector proteins and mediate outside-in signaling process.Protein phosphatase 2A (PP2A) is a serine/threonine (Ser/ Thr) phosphatase that regulate cell growth, development, and apoptosis. PP2A holoenzyme contains the catalytic subunit C (PP2Ac) and the structural or scaffolding subunit A (PP2Aa). The A subunit of PP2A interacts with multiple regulatory B subunits and regulates the subcellular localization, substrate specificity, and the catalytic activity of PP2A (5). Although, PP2Ac exhibit ␣ and ␤ isoforms, a 10-fold abundant expression of PP2Ac␣ in most cell types (6) had led us to consider PP2Ac␣ in our previous integrin studies (4). These studies revealed that the depletion of PP2Ac␣ in 293 ␣ IIb ␤ 3 cells resulted in an enhanced adhesion to immobilized fibrinogen (4). However, an underlying mechanism is incompletely understood.Alternative model systems like 293 ␣ IIb ␤ 3 cells or Chinese Hamster Ovary (CHO) ␣ IIb ␤ 3 cells have proved useful in elucidating the signaling properties of integrin ␣ IIb ␤ 3 (7-9). In particular, such models are appealing if the role of the signaling molecules under study will be deciphered using a genetic approach. In the context of this study, embryonic lethality of PP2Ac␣-null mice (10), lack of a specific PP2Ac␣ pharmacological inhibitor, and the non feasibility of gene expression in anucleate platelets have limited the extensive use of platelets. The aim of this study in 293 ␣ IIb ␤ 3 cells was to elucidate the molecular events that underpin the PP2Ac␣ mediated negative regulation of ␣ IIb ␤ 3 cell adhesion. In particular; we wished to examine the regulation of c-Src activity (referred to as Src in this manuscript) by PP2Ac␣. c-Src signaling constitutes one of the early signaling events in the outside-in ␣ IIb ␤ 3 signaling process (11).In this study, we identified that loss of PP2Ac␣ activated Src via PTP-1B. Furthermore, Src and PTP-1B activity was required for the enhanced adhesive phenotype displayed by the PP2Ac␣-depleted 293 ␣ IIb ␤ 3 cells. * This work was supported, in whole or in part...

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Section: Discussionmentioning

confidence: 99%

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Pradhan

Alrehani

Patel

et al. 2010

Journal of Biological Chemistry

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“…Previous reports and our data have shown that serine/threonine phosphatase activities are needed for an agonist to initiate platelet secretion, aggregation and thromboxane synthesis, since okadaic acid, a potent inhibitor of PP1 and PP2A, inhibits platelet functions ( fig. 3) [25]. However PKC activity was hardly affected.…”

Section: Signalling Metabolites and Platelet Pathologymentioning

confidence: 95%

Platelet Signal Transduction Pathways: Could We Organize Them into a ‘Hierarchy’?

Lévy-Toledano

1999

Pathophysiol Haemos Thromb

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Platelet activation results in shape change, release of granule contents, aggregation and clot retraction. An intense intracellular ‘machinery’ is engaged to achieve these functions. Thrombin is one of the most important agonists for platelet recruitment and aggregation which is mediated by the binding of fibrinogen to its adhesive receptor: the glycoprotein (GP) IIb/IIIa complex or integrin αIIbβ₃. The numerous biological processes consecutive to thrombin binding to platelet membrane are mainly controlled by phosphorylation mechanisms organized into signalling pathways. Schematically, the phospholipase Cβ pathway activated by G protein coupled to the seven transmembrane thrombin receptors, provides the first intracellular relay and would generate regulators such as protein kinase C, phosphorylated pleckstrin but also modifications of the intracellular domain of β₃. This inside-out signalling would lead to some changes in the extracellular domain of GPIIb/IIIa increasing access of fibrinogen to the receptor. Ligand interaction with GPIIb/IIIa induced reorganization of the cytoskeleton and would mediate the outside-in signals which involve a series of intracellular events including tyrosine kinases, phosphatidylinositol 3 kinases, MAP kinases and phosphatases. Some of these pathways and/or signalling metabolites could be associated to some well-characterized platelet functions: cortactin phosphorylation is involved in platelet shape change, phosphatidylinositol 3 kinase (p85) in the stabilisation of platelet aggregates and MAP kinase (p44) in postaggregation events. But in fact the sequence of events which has been described has to be viewed as integrated networks. At least three biochemical processes govern the highly integrated organization to send just the appropriate quanta of signal for a specific need: the reorganisation of the cytoskeleton following the binding of fibrinogen to αIIbβ₃, the structure of the signal transducers that contain SH2, SH3, and PH domains leading to the formation of macromolecules of signalling and the crosstalk phenomena between the different pathways. Elucidating the mechanisms of such networks becomes an increasingly exciting project.

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“…Previously, our laboratory had shown that serine residues on the cytoplasmic domain of E-selectin became de-phosphorylated upon HL-60 adhesion (6). There have been reports that serine/threonine dephosphorylation may be involved in the subsequent tyrosine phosphorylation (35). We are in the process of determining whether cross-linking-induced dephosphorylation on serine residues is required for the observed phosphorylation on tyrosine residues in the cytoplasmic domain of E-selectin.…”

Section: Figmentioning

confidence: 99%

Molecular Events in Transmembrane Signaling via E-selectin

Szente

Kíely

et al. 2001

Journal of Biological Chemistry

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E-selectin is a cytokine-inducible adhesion molecule that is expressed by activated endothelial cells at sites of inflammation. In addition to supporting rolling and stable arrest of leukocytes, there is increasing evidence that E-selectin functions in transmembrane signaling into endothelial cells during these adhesive interactions. We have previously shown that adhesion of HL-60 cells (which express ligands for E-selectin), or antibodymediated cross-linking of E-selectin, results in formation of a Ras/Raf-1/phospho-MEK macrocomplex, extracellular signal-regulated protein kinase (ERK1/2) activation, and c-fos up-regulation. All of these downstream signaling events appear to require an intact cytoplasmic domain of E-selectin. Here we demonstrate that tyrosine 603 in the cytoplasmic domain of E-selectin is required for the E-selectin-dependent ERK1/2 activation. Tyrosine 603 plays an important role in mediating the association of E-selectin with SHP2, and the catalytic domain of SHP2 is, in turn, critical for E-selectin-dependent ERK1/2 activation. An adapter protein complex consisting of Shc⅐Grb2⅐Sos bridges between SHP2 and the Ras⅐Raf⅐phospho-MEK macrocomplex. These molecular events thus outline a mechanism by which cross-linking of E-selectin by engagement of ligands on adherent leukocytes can initiate a multifunctional signaling pathway in the activated endothelial cell at sites of inflammation. E-selectin is an inducible adhesion molecule that is expressed at relatively high density on the surface of cultured endothelial cells that have been activated by proinflammatory cytokines, such as interleukin-1b (IL-1␤), 1 tumor necrosis factor-␣, or bacterial endotoxin. It is detectable in vivo at the sites of inflammation (1-3). In addition to supporting the rolling and stable arrest of leukocytes on activated endothelium, there is increasing evidence that E-selectin can transduce outside-in signals (4 -6). Recently our laboratory demonstrated that leukocyte adhesion to cell surface E-selectin-activated extracellular signal-regulated protein kinase (ERK1/2), formed a macrocomplex containing Ras/Raf-1/phospho-MEK, and resulted in the up-regulation of c-fos expression (7). In this study, we have investigated the molecular events occurring immediately upstream of Ras/Raf/phospho-MEK and downstream of cell surface E-selectin. The cytoplasmic domain of E-selectin has been implicated in transmembrane signaling (5, 7); however, the molecular mechanisms involved have not been well defined. The cytoplasmic domain of E-selectin consists of 32 amino acids (1), including two tyrosine residues. It has been well documented that phosphorylation of tyrosine residues in the cytoplasmic domains of various types of receptors can play an important role in receptor-mediated transmembrane signal transduction, especially ERK1/2 activation. Therefore, it is reasonable to hypothesize that the two tyrosine residues on the cytoplasmic domain of E-selectin may be involved in the E-selectin-dependent ERK1/2 activation described by our laborat...

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Serine/Threonine Dephosphorylation May Be Involved in Tyrosine Phosphorylation: A New Mode of Signal Transduction in Platelets

Cited by 11 publications

References 35 publications

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Cross-talk between Serine/Threonine Protein Phosphatase 2A and Protein Tyrosine Phosphatase 1B Regulates Src Activation and Adhesion of Integrin αIIbβ3 to Fibrinogen

Platelet Signal Transduction Pathways: Could We Organize Them into a ‘Hierarchy’?

Molecular Events in Transmembrane Signaling via E-selectin

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