Involvement of Protein Phosphatase 2A in the Interleukin-3-Stimulated Jak2-Stat5 Signaling Pathway

Yokoyama, Noriko; Reich, Nancy C.; Miller, W. Todd

doi:10.1089/107999001750277844

Cited by 42 publications

(28 citation statements)

References 53 publications

(119 reference statements)

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“…However, PP2A can be turned "on" and "off" by subunit phosphorylation and carboxyl methylation in addition to binding of the various regulatory subunits as described for Src-related kinase p56 Lck , insulin receptor, and the EGF receptor (42-44). Furthermore, IL-3 modulation of PP2A activity has been described for Jak2 (45), anti-apoptotic protein Bcl-2 (46), and Raf1 kinase (47). Since PP2A does not bind the Fc␣RI-S263A mutant in yeast, representing the active receptor, and PP2A activity increased upon IL-3 stimulation, we suggest PP2A to become more active upon cytokine stimulation, resulting in Fc␣RI dephosphorylation and dissociation of PP2A from the receptor.…”

Section: Discussionmentioning

confidence: 55%

Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Bakema

Bakker

Haij

et al. 2008

The Journal of Immunology

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To achieve a correct cellular immune response toward pathogens, interaction between FcR and their ligands must be regulated. The Fc receptor for IgA, FcαRI, is pivotal for the inflammatory responses against IgA-opsonized pathogens. Cytokine-induced inside-out signaling through the intracellular FcαRI tail is important for FcαRI-IgA binding. However, the underlying molecular mechanism governing this process is not well understood. In this study, we report that PP2A can act as a molecular switch in FcαRI activation. PP2A binds to the intracellular tail of FcαRI and, upon cytokine stimulation, PP2A becomes activated. Subsequently, FcαRI is dephosphorylated on intracellular Serine 263, which we could link to receptor activation. PP2A inhibition, in contrast, decreased FcαRI ligand binding capacity in transfected cells but also in eosinophils and monocytes. Interestingly, PP2A activity was found crucial for IgA-mediated binding and phagocytosis of Neisseria meningitidis. The present findings demonstrate PP2A involvement as a molecular mechanism for FcαRI ligand binding regulation, a key step in initiating an immune response.

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Section: Discussionmentioning

confidence: 55%

Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Bakema

Bakker

Haij

et al. 2008

The Journal of Immunology

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“…It is possible that there is another phosphatase(s) involved in the dephosphorylation of Stat5A. Previous studies with overexpression systems have suggested that other phosphatases, PTP1B (26), TC-PTP (27), and phosphatase 2A (28), in addition to Shp-2 (25), are able to interact and dephosphorylate Stat5A. However, the physiological role of these phosphatases in down-regulation of Stat5A is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the fact that these two proteasome inhibitors dramatically stabilize the tyrosine-phosphorylated Stat5, there is no direct evidence to support a notion that protein degradation is responsible for the down-regulation of active Stat5 (24). Previous studies with overexpression systems have suggested that several phosphatases, including Shp-2 (25), PTP1B (26), TC-PTP (27), and phosphatase 2A (28), are able to interact and dephosphorylate Stat5A; however, the physiological role of these phosphatases in down-regulation of Stat5A is not clear. In this report, we address the key unanswered question regarding Stat5A down-regulation and identify Shp-2 as a Stat5A phosphatase.…”

mentioning

confidence: 99%

Identification of Shp-2 as a Stat5A Phosphatase

Chen

Wen

Yang

et al. 2003

Journal of Biological Chemistry

109

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Stat5A, a member of the signal transducers and activators of transcription (Stat) family, is activated upon a single tyrosine phosphorylation. Although much is known about the activation process, the mechanism by which the tyrosine-phosphorylated Stat5A proteins are inactivated is largely unknown. In this report, we demonstrate that down-regulation of the tyrosine-phosphorylated Stat5A was via dephosphorylation. Using tyrosine-phosphorylated peptides derived from Stat5A, we were able to purify protein-tyrosine phosphatase Shp-2 from cell lysates. Shp-2, but not Shp-1, specifically interacted with Stat5A in vivo, and the interaction was tyrosine phosphorylation-dependent. Moreover, Shp-2 was able to accelerate Stat5A dephosphorylation, and dephosphorylation of Stat5A was dramatically delayed in Shp-2-deficient cells. Therefore, we conclude that Shp-2 is a Stat5A phosphatase, which down-regulates the active Stat5A in vivo.

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“…9,10 On the other hand, JAK2 constitutive activity 49,50 and SETBP1 overexpression in BCR/ABL-negative AML 37 might independently contribute to PP2A inactivation. Our results show that the mechanisms of PP2A inactivation in AML might be the overexpression of the physiological PP2A inhibitors CIP2A 33 and SET, 51 the overexpression of SETBP1, or the downregulation of PP2A subunits, suggesting that dysfunction of several distinct PP2A complexes may contribute to cell transformation.…”

Section: Pp2a Inhibition In Aml I Cristóbal Et Almentioning

confidence: 99%

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

et al. 2011

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Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML.

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Involvement of Protein Phosphatase 2A in the Interleukin-3-Stimulated Jak2-Stat5 Signaling Pathway

Cited by 42 publications

References 53 publications

Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Inside-Out Regulation of FcαRI (CD89) Depends on PP2A

Identification of Shp-2 as a Stat5A Phosphatase

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

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