p38 mitogen‐activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen

Sundaresan, Pavithra; Farndale, Richard W.

doi:10.1016/s0014-5793(02)03277-5

Cited by 43 publications

(43 citation statements)

References 37 publications

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“…We also have shown that tyrosine phosphatase inhibitors did not block p38 MAP kinase activity. This is in contrast to other reports that suggest that protein phosphatases act as negative regulators of MAP kinases (72,73). Taken together, these findings suggest that p38 MAP kinase and SHP2 mediate HCV-E2-and HIV-gp120-induced IL-8 production.…”

Section: Discussioncontrasting

confidence: 95%

Hepatitis C Virus and HIV Envelope Proteins Collaboratively Mediate Interleukin-8 Secretion through Activation of p38 MAP Kinase and SHP2 in Hepatocytes

Balasubramanian

Ganju

Groopman

2003

Journal of Biological Chemistry

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Hepatitis C virus (HCV) infects ϳ40% of human immunodeficiency virus (HIV) patients, and the resulting hepatic dysfunction that occurs is the primary cause of death in patients with co-infection. We hypothesized that hepatocytes exposed to HCV and HIV proteins might be susceptible to injury via an "innocent bystander" mechanism. To assess this, we studied the effects of envelope proteins, E2 of HCV and gp120 of HIV, in model HepG2 cells. Upon co-stimulation with HCV-E2 and HIV-gp120, we observed a potent proinflammatory response with the induction of IL-8. Furthermore, our studies revealed that HCV-E2 and HIV-gp120 act collaboratively to trigger a specific set of downstream signaling pathways that include activation of p38 mitogenactivated protein (MAP) kinase and the tyrosine phosphatase, SHP2. Both specific inhibitors of p38 MAP kinase and sodium vanadate, a potent protein-tyrosine phosphatase inhibitor, blocked IL-8 production in a dosedependent manner. The role of p38 MAP kinase and SHP2 was further defined by transiently overexpressing dominant negative mutants of these proteins into HepG2 cells. These studies revealed that overexpression of an inactive p38 MAP kinase or SHP2 mutant partially abrogated HCV-E2-and HIV-gp120-induced IL-8 production. Further studies revealed that IL-8 induction was not mediated through activation of the NF-B pathway. However, HCV-E2 plus HIV-gp120 was shown to increase the DNA binding activity of AP-1. These results emphasize that expression of the proinflammatory chemokine IL-8, induced by HCV-E2 and HIV-gp120, may be mediated through p38 MAP kinase and SHP2 in an NF-B-independent manner, albeit through AP-1-driven processes.

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Section: Discussioncontrasting

confidence: 95%

Hepatitis C Virus and HIV Envelope Proteins Collaboratively Mediate Interleukin-8 Secretion through Activation of p38 MAP Kinase and SHP2 in Hepatocytes

Balasubramanian

Ganju

Groopman

2003

Journal of Biological Chemistry

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“…SB203580, instead, increased pERK without inducing musclespecific gene expression. Note that SB203580 induced an increase in the levels of pp38, probably through the inhibition of a self-regulatory loop mediated by a p38-activated protein phosphatase 2A (Sundaresan and Farndale, 2002). Indeed, treatment of QMb-LA29 in DM at 351C with okadaic acid (100 nM), a specific inhibitor of protein phosphatase 2A, induced a significant increase in the level of p38 phosphorylation (not shown).…”

Section: Resultsmentioning

confidence: 90%

Delineating v-Src downstream effector pathways in transformed myoblasts

et al. 2007

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“…20 Consistent with the inhibition of collagen-induced platelet activation, 19 GPVI dimerization was blocked by PAO, a commonly used inhibitor of Tyr phosphatases. 26 Protein disulfide isomerase inhibition by PAO was ruled out by the absence of effect of bacitracin (3 mol/L) on 9E18 binding (data not shown).…”

Section: Discussionmentioning

confidence: 97%

Platelet Glycoprotein VI Dimerization, an Active Process Inducing Receptor Competence, Is an Indicator of Platelet Reactivity

Loyau

Dumont

Ollivier

et al. 2012

ATVB

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Objective-The immune receptor homologue glycoprotein VI (GPVI)/FcR receptor ␥ chain complex is primarily responsible for platelet activation by collagen. There is growing evidence that optimal binding of GPVI to collagen depends on the assembly of GPVI dimers. The valence of GPVI on resting platelets needs to be clearly established because platelet avidity for collagen would be greater if GPVI is constitutively expressed as a dimer than as a monomer. Methods and Results-Using a monoclonal antibody (9E18) that preferentially binds to GPVI dimers, we found that GPVI was maintained in a monomeric form on human resting platelets under the control of intraplatelet cAMP concentration. Activation by soluble agonists or von Willebrand factor induced a shift toward GPVI dimerization related to increased platelet adhesion to collagen. A correlation between platelet binding of 9E18 and P-selectin exposure was observed in patients experiencing coronary artery disease, and antagonists of the ADP receptor P2Y 12 limited ADP-induced GPVI dimerization. Key Words: antiplatelet drugs Ⅲ collagen Ⅲ monoclonal antibodies Ⅲ platelets Ⅲ glycoprotein VI P latelet adhesion at sites of vascular damage is required for normal hemostasis. Circulating platelets adhere to proteins of the subendothelial matrix exposed by vessel injury in a process involving several receptors. Collagen fibers are highly thrombogenic, and the platelet glycoprotein VI (GPVI) predominantly mediates collagen-induced platelet responses. Conclusion-TheGPVI is a platelet-specific receptor of the immunoglobulin (Ig) superfamily containing 2 extracellular Ig domains, a single transmembrane domain, and a short cytoplasmic tail. [1][2][3] GPVI shares with other receptors of the same family the particularity that the extracellular ligand-binding domain and the intracellular signaling domain are on separate subunits. GPVI signals through the noncovalently associated immune receptor adaptor FcR␥. 4 The receptor is assembled via a transmembrane interaction between Asp11 in the FcR␥ homodimer and Arg273 of GPVI. On stimulation, the Tyr residues of the immunoreceptor tyrosine-based activation motif of FcR␥ are phosphorylated in an early, obligatory event triggering the signaling cascade. See accompanying article on page 552There is growing evidence that optimal binding of GPVI to collagen depends on the formation of GPVI dimers at the platelet surface. Miura et al, 5 using recombinant proteins, were the first to report that collagen binds to the dimeric form but not to the monomeric form of GPVI and that only the former was able to inhibit collagen-induced platelet activation. Crystallographic data showing dimerization of GPVI ectodomains, 6 studies using synthetic peptides with differentially spaced GPVI binding motifs to activate the receptor in platelets, 7 and studies using chemical cross-linking agents 8 have strongly reinforced the notion that GPVI functions as a dimer. However, the valence of GPVI on resting and on activated platelets is still a matter of debate. It was ...

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p38 mitogen‐activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen

Cited by 43 publications

References 37 publications

Hepatitis C Virus and HIV Envelope Proteins Collaboratively Mediate Interleukin-8 Secretion through Activation of p38 MAP Kinase and SHP2 in Hepatocytes

Hepatitis C Virus and HIV Envelope Proteins Collaboratively Mediate Interleukin-8 Secretion through Activation of p38 MAP Kinase and SHP2 in Hepatocytes

Delineating v-Src downstream effector pathways in transformed myoblasts

Platelet Glycoprotein VI Dimerization, an Active Process Inducing Receptor Competence, Is an Indicator of Platelet Reactivity

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