The Tumor Suppressor PTEN Regulates T Cell Survival and Antigen Receptor Signaling by Acting as a Phosphatidylinositol 3-Phosphatase

Wang, Xiaodong; Gjörloff-Wingren, Anette; Saxena, Manju; Pathan, Nuzhat; Reed, John C.; Mustelin, Tomas

doi:10.4049/jimmunol.164.4.1934

Cited by 66 publications

(47 citation statements)

References 21 publications

(44 reference statements)

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“…However, critical intermediate signal transduction events require further study. Candidate signaling intermediates include inducible T cell kinase, which may act both upstream and downstream of PI3K; AKT, which influences cell survival through up-regulation of Bcl-x L in an NF-Bdependent mechanism; and p27 KIP , a negative regulator of cell cycle progression (51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Furthermore, HIV-1 expression correlates with increased T cell apoptosis and disruption of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of Phosphatidylinositol 3-Kinase to CD28 Inhibits HIV Transcription by a Tat-Dependent Mechanism

Cook¹,

August

Henderson

2002

The Journal of Immunology

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Activation through the TCR and the costimulatory molecule CD28 influences the susceptibility of T cells to HIV-1 infection and regulates proviral gene expression. Signaling events initiated by CD28 that directly impact HIV-1 transcription have not been fully characterized. T cell lines expressing CD8α/28 chimeric receptors containing a mutation in tyrosine 173 to phenylalanine, which inhibits the recruitment of phosphatidylinositol 3-kinase (PI3K) to CD28, expressed higher levels of HIV-1 following T cell activation. Whereas constitutively active PI3K decreased provirus transcription, inhibiting endogenous PI3K with specific inhibitors or by overexpressing PTEN phosphatase enhanced HIV-1 expression. PI3K-dependent inhibition required the viral Tat protein and a trans activation response region element. Tat pull-down and coimmunoprecipitation experiments indicate that PI3K affects the formation of the Tat-associated kinase trans-activating complex. These studies demonstrate that PI3K negatively impacts HIV-1 transcription and that Tat activity is sensitive to T cell signaling events.

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Section: Discussionmentioning

confidence: 99%

Recruitment of Phosphatidylinositol 3-Kinase to CD28 Inhibits HIV Transcription by a Tat-Dependent Mechanism

Cook¹,

August

Henderson

2002

The Journal of Immunology

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“…However, this did not have any significant impact on the experimental results, and this step was therefore omitted in later experiments. Experiments were also performed with Jurkat cells, as before (12,20).…”

Section: Methodsmentioning

confidence: 99%

Cooperative Phosphorylation of the Tumor Suppressor Phosphatase and Tensin Homologue (PTEN) by Casein Kinases and Glycogen Synthase Kinase 3β

Al-Khouri¹,

Togo³

et al. 2005

Journal of Biological Chemistry

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The phosphatase and tensin homologue (PTEN) tumor suppressor is a phosphatidylinositol D3-phosphatase that counteracts the effects of phosphatidylinositol 3-kinase and negatively regulates cell growth and survival. PTEN is itself regulated by phosphorylation on multiple serine and threonine residues in its C terminus. Previous work has implicated casein kinase 2 (CK2) as the kinase responsible for this phosphorylation. Here we showed that CK2 does not phosphorylate all sites in PTEN and that glycogen synthase kinase 3␤ (GSK3␤) also participates in PTEN phosphorylation. Although CK2 mainly phosphorylated PTEN at Ser-370 and Ser-385, GSK3␤ phosphorylated Ser-362 and Thr-366. More importantly, prior phosphorylation of PTEN at Ser-370 by CK2 strongly increased its phosphorylation at Thr-366 by GSK3␤, suggesting that the two may synergize. Using RNA interference, we showed that GSK3 phosphorylates PTEN in intact cells. Finally, PTEN phosphorylation was affected by insulin-like growth factor in intact cells. We concluded that multiple kinases, including CK2 and GSK3␤, participate in PTEN phosphorylation and that GSK3␤ may provide feedback regulation of PTEN. Phosphatase and tensin homologue (PTEN)2 (1-3) is a tumor suppressor that is frequently mutated in human cancers (4 -8). The 55-kDa PTEN protein was originally described as a dual-specificity protein phosphatase, but biochemical studies soon showed that PTEN was a poor protein phosphatase but an efficient phosphoinositide D3-phosphatase (9). In cells, PTEN acts as a tumor suppressor by antagonizing phosphoinositide 3-kinase (PI3K), which activates the Akt Ser/Thr kinase, which in turn activates proliferative and antiapoptotic signaling pathways (10 -14).Posttranslationally, PTEN is regulated through phosphorylation of a cluster of serine and threonine residues in its C terminus (15-21).Although not required for the activity of the catalytic domain, phosphorylation of the C-terminal region plays an important role in stabilizing the PTEN protein. In its phosphorylated form, the tail is thought to wrap unto the C2 and catalytic domains of PTEN and thereby block the translocation of PTEN to the cytoplasmic face of the plasma membrane (16,22), thus effectively inhibiting the dephosphorylation of the substrates of PTEN. Tail mutants of PTEN tend to have increased catalytic activity but are rapidly degraded in cells.Using a mutagenesis approach, Torres and Pulido (17) showed that the C-terminal region of PTEN is constitutively phosphorylated in vivo between residues 369 and 386, mostly on Ser-370 and Ser-385. They also found that the Ser/Thr protein kinase casein kinase 2 (CK2) can phosphorylate these residues in vitro as well as, to a lower extent, Ser-380, . Vazquez et al. (16) also found that all phosphorylation of PTEN occurred in the C-terminal region (residues 354 -403) and identified Ser-370 plus at least one other residue (Ser-380, Thr-382, Thr-383, or Ser-385) as the sites in vivo. They also reported that mutation of Ser-380, Thr-382, or Thr-383 to alanine redu...

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“…In Jurkat cells the lack of PTEN manifests itself as a constitutively elevated level of D3-phosphoinositides and increased activity of enzymes that depend on these lipids, such as the Itk tyrosine kinase (17). Reconstitution of PTEN expression reduced cell survival by inducing apoptosis (6). This effect was prevented by a constitutively active form of protein kinase B (PKB), 3 one of the bestcharacterized effectors for phosphatidylinositol 3-kinase (18,19).…”

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confidence: 99%

Negative Feedback Regulation of the Tumor Suppressor PTEN by Phosphoinositide-Induced Serine Phosphorylation

Birle¹,

Bottini²,

Williams³

et al. 2002

The Journal of Immunology

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The PTEN tumor suppressor phosphatase directly counteracts the multiple functions of phosphatidylinositol 3-kinase by removing phosphate from the D3 position of inositol phospholipids. Like many lymphomas and leukemias, the Jurkat T cell line lacks PTEN protein due to frame-shift mutations in both PTEN alleles and therefore survives in long-term cell culture. We report that PTEN reintroduced into Jurkat was highly phosphorylated on serines 380 and 385 in its C terminus, particularly the former site. Phosphate was also detected at Ser380 in PTEN in untransformed human T cells. Treatments that reduced the levels of D3-phospholipids in the cells resulted in reduced phosphorylation and accelerated degradation of PTEN. In contrast, expression of inactive PTEN-C124G or coexpression of a constitutively active protein kinase B led to increased phosphorylation and slower degradation of PTEN. These results suggest that PTEN normally is subjected to a feedback mechanism of regulation aimed at maintaining homeostatic levels of D3-phosphoinositides, which are crucial for T cell survival and activation.

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The Tumor Suppressor PTEN Regulates T Cell Survival and Antigen Receptor Signaling by Acting as a Phosphatidylinositol 3-Phosphatase

Cited by 66 publications

References 21 publications

Recruitment of Phosphatidylinositol 3-Kinase to CD28 Inhibits HIV Transcription by a Tat-Dependent Mechanism

Recruitment of Phosphatidylinositol 3-Kinase to CD28 Inhibits HIV Transcription by a Tat-Dependent Mechanism

Cooperative Phosphorylation of the Tumor Suppressor Phosphatase and Tensin Homologue (PTEN) by Casein Kinases and Glycogen Synthase Kinase 3β

Negative Feedback Regulation of the Tumor Suppressor PTEN by Phosphoinositide-Induced Serine Phosphorylation

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