Protein Phosphatase 1 Associates with the Integrin αIIb Subunit and Regulates Signaling

Vijayan, K. Vinod; Liu, Yan; Li, Tongtong; Bray, Paul F.

doi:10.1074/jbc.c400239200

Cited by 51 publications

(62 citation statements)

References 28 publications

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“…This observation is consistent with a previous study that showed an association of the inhibitor for PP2A (I1PP2A) with the membrane proximal GFFKR motif of integrin ␣ 3A ␤ 1 (24). The membrane proximal region of ␣ IIb can host the binding of calcium and integrinbinding protein 1, PP1c, and ICIn (8,25,26); therefore, it is conceivable that only a subpopulation of ␣ IIb ␤ 3 may harbor PP2Ac. Because GFFKR sequence is conserved in other ␣ subunits, it is likely that PP2Ac association may not be limited to ␣ IIb subunits.…”

Section: Discussionsupporting

confidence: 80%

“…In resting platelets, a pool of the catalytic subunit of protein phosphatase 1 (PP1c) constitutively associates with ␣ IIb ␤ 3 complex (8). Studies from other cell types have revealed that PP2Ac can associate with integrin ␤ 1 (19).…”

Section: Resultsmentioning

confidence: 99%

“…For instance, c-Src associates constitutively to the ␤ 3 tail (4). Fibrinogen binding to ␣ IIb ␤ 3 induces association of protein tyrosine phosphatase 1B, spleen tyrosine kinase, and protein kinase C␤ to the ␤ 3 tail (4 -6) and calcium and integrin-binding protein 1 to the ␣ IIb tail (7) and causes the dissociation of C terminus Src kinase from the ␤ 3 tail (4) and the catalytic subunit of protein phosphatase 1 (PP1c) 6 from the ␣ IIb tail (8). Reversible phosphorylation of multiple effector proteins that are downstream of the integrin signaling pathway is one of the mechanisms by which these ␣ IIb ␤ 3 -associated proteins can initiate and/or transduce signals.…”

mentioning

confidence: 99%

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Protein Phosphatase 2A Negatively Regulates Integrin αIIbβ3 Signaling

Gushiken¹,

Patel

Liu³

et al. 2008

Journal of Biological Chemistry

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Integrin ␣ IIb ␤ 3 activation is critical for platelet physiology and is controlled by signal transduction through kinases and phosphatases. Compared with kinases, a role for phosphatases in platelet integrin ␣ IIb ␤ 3 signaling is less understood. We report that the catalytic subunit of protein phosphatase 2A (PP2Ac) associates constitutively with the integrin ␣ IIb ␤ 3 in resting platelets and in human embryonal kidney 293 cells expressing ␣ IIb ␤ 3 . The membrane proximal KVGFFKR sequence within the cytoplasmic domain of integrin ␣ IIb is sufficient to support a direct interaction with PP2Ac. Fibrinogen binding to ␣ IIb ␤ 3 during platelet adhesion decreased integrinassociated PP2A activity and increased the phosphorylation of a PP2A substrate, vasodilator associated phosphoprotein. Overexpression of PP2Ac ␣ in 293 cells decreased ␣ IIb ␤ 3 -mediated adhesion to immobilized fibrinogen. Conversely, small interference RNA mediated knockdown of endogenous PP2Ac ␣ expression in 293 cells, enhanced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and accelerated ␣ IIb ␤ 3 adhesion to fibrinogen and von Willebrand factor. Inhibition of ERK1/2, but not p38 activation, abolished the increased adhesiveness of PP2Ac ␣ -depleted 293 cells to fibrinogen. Furthermore, knockdown of PP2A c␣ expression in bone marrow-derived murine megakaryocytes increased soluble fibrinogen binding induced by protease-activated receptor 4-activating peptide. These studies demonstrate that PP2Ac ␣ can negatively regulate integrin ␣ IIb ␤ 3 signaling by suppressing the ERK1/2 signaling pathway.Integrin cytoplasmic tails are devoid of any intrinsic catalytic activity. Nevertheless, integrins can transmit bidirectional signals across the plasma membrane of a cell and regulate several cellular processes, such as, adhesion, migration, and apoptosis. In the context of the major platelet integrin ␣ IIb ␤ 3 , emerging evidence indicates that cytoplasmic tails act as a molecular scaffold for intracellular enzymes and for both cytoskeletal and adaptor proteins and can either positively or negatively regulate signaling (1). For example, during an agonist-mediated insideout signaling process, talin interacts with the integrin ␤ 3 tail and induces integrin ␣ IIb ␤ 3 activation (2), whereas calcium and integrin-binding protein 1 binds to the ␣ IIb tail and negatively regulates ␣ IIb ␤ 3 activation (3).Subsequent binding of fibrinogen to the activated ␣ IIb ␤ 3 integrin initiates an outside-in signaling process that regulates platelet function. Outside-in signaling can be mediated by intricate interplay of a set of proteins that associate constitutively with the integrin and by others that either associate or dissociate with the integrin in response to fibrinogen binding. For instance, c-Src associates constitutively to the ␤ 3 tail (4). Fibrinogen binding to ␣ IIb ␤ 3 induces association of protein tyrosine phosphatase 1B, spleen tyrosine kinase, and protein kinase C␤ to the ␤ 3 tail (4 -6) and calcium and integrin-binding protein 1 to t...

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Protein Phosphatase 2A Negatively Regulates Integrin αIIbβ3 Signaling

Gushiken¹,

Patel

Liu³

et al. 2008

Journal of Biological Chemistry

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“…Interestingly, fostriecin had no effect on the elevation of p38 MAPK phosphorylation found in Pro33 cells, though the PP1/PP2A inhibitor okadaic acid was effective. Thus, we suspect that PP1 activation downstream of Pro33 may be responsible for p38 MAPK activation, whereas transmission of kinase activation to SERT upregulation involves PP2A ( Figure 6C) (34). Student's t test: *P < 0.05; 1-way ANOVA with Dunnett's post-test: # P < 0.05; n = 6.…”

Section: Discussionmentioning

confidence: 99%

Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

Carneiro

Cook²,

Murphy³

et al. 2008

J. Clin. Invest.

168

130

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The essential contribution of the antidepressant-sensitive serotonin (5-HT) transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores suggests an important role of this transporter in platelet function. Here, using SERT-deficient mice, we have established a role for constitutive SERT expression in efficient ADPand thrombin-triggered platelet aggregation. Additionally, using pharmacological blockers of SERT and the vesicular monoamine transporter (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in efficient human platelet aggregation. We have also demonstrated that fibrinogen, an activator of integrin αIIbβ3, enhances SERT activity in human platelets and that integrin αIIbβ3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin β3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin β3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of αIIbβ3/SERT associations as well as αIIbβ3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.

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“…PP2A, in turn, plays a critical role in αIIbβ3-mediated cell adhesion Integrin mediated cell adhesion is known to induce changes in PP2A activity [18] and localization within integrin-organized focal adhesion complex through its interaction with paxillin [19]. Instructively, the activity of αIIbβ3 has been shown to regulate phosphatase PP1 [20]. The association of both PP1 and PP2A with αIIb and β3, respectively, highlights the importance of phosphatases in the regulation of integrin signaling.…”

Section: Discussionmentioning

confidence: 99%

Increased activity of phosphatase PP2A in the presence of the PlA2 polymorphism of αIIbβ3

Wang

Yan

Satterwhite

et al. 2008

Biochemical and Biophysical Research Communications

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Polymorphisms in αIIbβ3 are important genetic factors that alter platelet biology and have been associated with susceptibility to thromboembolic disorders. To define the molecular mechanisms that lead to variance in thrombotic diathesis dictated by the β3 polymorphism, we examined regulation of intracellular signaling by αIIbβ3, and studied the effects of a common β subunit PlA2 polymorphism. We found that PP2A regulates αIIbβ3 control of the ERK signaling in a polymorphism specific fashion. In CHO cells, exogenous expression of αIIbβ3 reduced ATPstimulated ERK phosphorylation and more so for PlA2 than PlA1. Interestingly, reduced level of ERK phosphorylation correlated with an increase in PP2A activity, with higher activity associated with PlA2 than PlA1. We tested the effect of PP2A on αIIbβ3-dependent adhesion, and found that PP2A overexpression increased cell adhesion, while phosphatase inhibitors decreased cell adhesion. We propose that PlA2 alters cell signaling at least in part by increasing β3-associated PP2A activity.

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Protein Phosphatase 1 Associates with the Integrin αIIb Subunit and Regulates Signaling

Cited by 51 publications

References 28 publications

Protein Phosphatase 2A Negatively Regulates Integrin αIIbβ3 Signaling

Protein Phosphatase 2A Negatively Regulates Integrin αIIbβ3 Signaling

Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

Increased activity of phosphatase PP2A in the presence of the PlA2 polymorphism of αIIbβ3

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