The Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB

Kandel, Eugene; Hay, Nissim

doi:10.1006/excr.1999.4690

Cited by 808 publications

(485 citation statements)

References 177 publications

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“…The 5-phosphatase and 3-phosphatase activities of PTPRQ may play complementary roles in inhibiting signaling via PI(3,4,5)P 3 produced by activated PI3-kinase. PI(3,4)P 2 (the product of 5-phosphatase activity) and PI(4,5)P 2 (the product of 3-phosphatase activity) are both less active in activating Akt͞PKB phosphorylation than is PI(3,4,5)P 3 (17). Thus, the 5-phosphatase p150Ship inhibits proliferation stimulated by macrophage colony-stimulating factor (29) and the related inositol 5-phosphatase SHIP2 is a negative regulator of signaling downstream of the insulin receptor (30).…”

Section: Discussionmentioning

confidence: 99%

“…The results above suggested that the sequence of WT PTPRQ adapts it to function as a PIPase rather than as a PTPase. To evaluate the ability of cytoPTPRQ to affect PIP levels in cultured cells, we evaluated the phosphorylation status of the serine͞threonine kinase Akt͞PKB, which is regulated by intracellular levels of PI(3,4,5)P 3 (17). The human glioblastoma cell lines U87MG and U373MG do not express the phosphatidylinositol 3-phosphatase PTEN (18,19), and we did not detect PTPRQ transcripts by RT-PCR (data not shown), or PTPRQ protein, by Western blot analysis with PTPRQ-specific antibody A429 (Fig.…”

Section: Expression Of Cytoptprq In Cultured Cells Reduces Phosphorylmentioning

confidence: 99%

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Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation

Oganesian

Poot

Daum

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Protein tyrosine phosphatase RQ (PTPRQ) was initially identified as a protein tyrosine phosphatase (PTPase)-like protein that is upregulated in a model of renal injury. Here we present evidence that, like PTEN, the biologically important enzymatic activity of PTPRQ is as a phosphatidylinositol phosphatase (PIPase). The PIPase specificity of PTPRQ is broader than that of PTEN and depends on different amino acid residues in the catalytic domain. In vitro, the recombinant catalytic domain of PTPRQ has low PTPase activity against tyrosine-phosphorylated peptide and protein substrates but can dephosphorylate a broad range of phosphatidylinositol phosphates, including phosphatidylinositol 3,4,5-trisphosphate and most phosphatidylinositol monophosphates and diphosphates. Phosphate can be hydrolyzed from the D3 and D5 positions in the inositol ring. PTPRQ does not have either of the basic amino acids in the catalytic domain that are important for the PIPase activity of PTEN or the sequence motifs that are characteristic of type II phosphatidylinositol 5-phosphatases. Instead, the PIPase activity depends on the WPE sequence present in the catalytic cleft of PTPRQ, and in the ''inactive'' D2 domains of many dual-domain PTPases, in place of the WPD motif present in standard active PTPases. Overexpression of PTPRQ in cultured cells inhibits proliferation and induces apoptosis. An E2171D mutation that retains or increases PTPase activity but eliminates PIPase activity, eliminates the inhibitory effects on proliferation and apoptosis. These results indicate that PTPRQ represents a subtype of the PTPases whose biological activities result from its PIPase activity rather than its PTPase activity.

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Section: Discussionmentioning

confidence: 99%

Section: Expression Of Cytoptprq In Cultured Cells Reduces Phosphorylmentioning

confidence: 99%

Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation

Oganesian

Poot

Daum

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Mice deficient in Akt display impeded PPAR␥ expression and adipogenesis (53). Akt and protein kinase A may also phosphorylate CREB (62)(63)(64), whereas ERK contributes to CREB-directed transcription, probably through recruitment of coactivators (54). Dominantnegative CREB inhibits hormone-induced adipocyte differentiation when expressed in preadipocytes, and ectopic expression of constitutively active CREB promotes adipogenesis (65).…”

Section: Galectin-12 In Adipogenesis3bmentioning

confidence: 99%

Galectin-12 Is Required for Adipogenic Signaling and Adipocyte Differentiation

Yang

Hsu

et al. 2004

Journal of Biological Chemistry

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“…Previous work suggested that rather than inhibit PI3K, the 3-deoxy-PI compounds inhibit the serine/ threonine protein kinase Akt by binding tightly to its PH domain, which normally binds PI(3,4) P 2 or PI (3,4,5), and trapping it in the cytoplasm, thereby preventing phosphorylation by effector kinases. 7 The spectrum of changes in cells caused by these 3-deoxy-PI molecules differs from other widely studied cell growth inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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D-3-Deoxy-phosphatidylinositol derivatives have cytotoxic activity against various human cancer cell lines. These phosphatidylinositols have a potentially wide array of targets in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling network. To explore the specificity of these types of molecules, we have synthesized D-3-deoxy-dioctanoylphosphatidylinositol (D-3-deoxydiC 8 PI), D-3,5-dideoxy-diC 8 PI and D-3-deoxy-dioctanoylphosphatidylinositol-5-phosphate and their enantiomers, characterized their aggregate formation by novel high resolution field cycling 31 P NMR, and examined their susceptibility to phospholipase C (PLC) and their effects on the catalytic activity of PI3K and PTEN against diC 8 PI and dioctanoylphosphatidylinositol-3-phosphate substrates, respectively, as well as their ability to induce the death of the U937 human leukemic monocyte lymphoma cells. Of these molecules, only D-3-deoxy-diC 8 PI was able to promote cell death; it did so with an IC 50 of 40 μM, well below the CMC of 0.4 mM. Under these conditions, there was little inhibition of PI3K or PTEN observed in assays of recombinant enzymes (although the complete series of deoxy-PI compounds did provide insights into ligand binding by PTEN). The D-3-deoxydiC 8 PI was a poor substrate and not an inhibitor of the PLC enzymes. The in vivo results are consistent with the current thought that the PI analogue acts on Akt1 since the transcription initiation factor eIF4e, which is a downstream signaling target of the PI3K/Akt pathway, exhibited reduced phosphorylation on Ser209. Phosphorylation of Akt1 on Ser473, but not Thr308, was reduced. Since the potent cytotoxicity for U937 cells is completely lost with the L-3-deoxy-diC 8 PI as well as with modification of the hydroxyl group at the inositol C5 (either replacing the -OH with a hydrogen or phosphorylating it) in D-3-deoxy-diC 8 PI, both chirality of the phosphoinositol moiety and the hydroxyl group at C5 are major determinants of 3-deoxy-PI binding to its target in cells.

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The Regulation and Activities of the Multifunctional Serine/Threonine Kinase Akt/PKB

Cited by 808 publications

References 177 publications

Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation

Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation

Galectin-12 Is Required for Adipogenic Signaling and Adipocyte Differentiation

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

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