TIP41 Interacts with TAP42 and Negatively Regulates the TOR Signaling Pathway

Jacinto, Estela; Guo, Bing; Arndt, Kim; Schmelzle, Tobias; Hall, Michael N.

doi:10.1016/s1097-2765(01)00386-0

Cited by 219 publications

(277 citation statements)

References 28 publications

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“…Thus, as with PP4C, PP4R2 appeared to be present in a complex with PP4R3␣ and/or PP4R3␤. In addition to these proteins, the PP4R2 pull-down also yielded MGC3794, the human homolog of S. cerevisiae Tip41 (Tap42-interacting protein, molecular mass of 42 kDa), a protein involved in rapamycin signaling through phosphatase regulation (33,34). We cloned the MGC3794 ORF (hereafter referred to as hTIP41) into the TAP tag vectors and repeated the pull-down/identification process with this fusion protein.…”

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confidence: 99%

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A Novel, Evolutionarily Conserved Protein Phosphatase Complex Involved in Cisplatin Sensitivity

Gingras

Caballero

Zarske

et al. 2005

Molecular & Cellular Proteomics

184

229

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Using a combination of tandem affinity purification tagging and mass spectrometry, we characterized a novel, evolutionarily conserved protein phosphatase 4 (PP4)-containing complex (PP4cs, protein phosphatase 4, cisplatin-sensitive complex) that plays a critical role in the eukaryotic DNA damage response. PP4cs is comprised of the catalytic subunit PP4C; a known regulatory subunit, PP4R2; and a novel protein that we termed PP4R3. The Saccharomyces cerevisiae PP4R3 ortholog Psy2 was identified previously in a screen for sensitivity to the DNAdamaging agent and anticancer drug cisplatin. We demonstrated that deletion of any of the PP4cs complex orthologs in S. cerevisiae elicited cisplatin hypersensitivity. Reversible protein phosphorylation is a highly conserved, essential regulatory mechanism involved in a host of cellular processes. Yet, while the phosphorylation of regulatory molecules by kinases has been studied intensively, their subsequent dephosphorylation is much less well understood. In eukaryotes, dephosphorylation on serine/threonine residues is effected by two distinct groups of functionally diverse phosphatases, the phosphoprotein M (represented by a sole member in higher eukaryotes, PP2C) and PPP 1 families (1 PP2A often functions as a standard trimeric complex with a catalytic (C) subunit (encoded by two genes in mammals) associated with one of many regulatory (or B) subunits via one of two adaptor (A) molecules (4, 5). The regulatory and adaptor subunits are thought to confer substrate specificity to the complex (5).In contrast to PP2A, the supramolecular architecture and subunit composition of PP4 multiprotein complexes remains largely unknown. Two mammalian PP4 regulatory subunits were previously identified (here termed PP4R1 and PP4R2, gene names PPP4R1 and PPP4R2; Refs. 6 and 7). Although PP4R1 shares some sequence homology with the PP2A adaptor proteins (PPP2R1A and PPP2R1B), it does not bridge PP4C and PP4R2; PP4R1 and PP4R2 display mutually exclusive PP4C interactions (Refs. 6 and 7; and see below). Other PP4C-interacting partners have also been reported (e.g. Refs. 8 and 9), but whether these proteins represent bona fide regulatory subunits or phosphatase substrates and how these binding proteins may affect PP4 activity are unclear.To gain a better understanding of the composition, function, and regulation of PP4, we systematically analyzed mammalian and yeast PP4C-interacting proteins. In doing so, we From the ‡Institute for

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confidence: 99%

“…This observation is intriguing because the yeast Tip41 protein was reported to interact with the yeast alpha4 homolog Tap42 and to prevent Tap42 from forming complexes with phosphatases (Ref. 33; see "Discussion"). Finally a pull-down of PP4R3␣ (KIAA2010) confirmed the interaction with PP4C and PP4R2.…”

Section: ; See Below)mentioning

confidence: 99%

A Novel, Evolutionarily Conserved Protein Phosphatase Complex Involved in Cisplatin Sensitivity

Gingras

Caballero

Zarske

et al. 2005

Molecular & Cellular Proteomics

184

229

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“…Moreover, studies in Saccharomyces cerevisiae are contributing significantly to our understanding of the Tor signal transduction pathway in eukaryotic cells. These studies have identified many of the downstream targets of Tor1/2 control as well as participants in the yeast signal transduction pathway itself, including peptidylprolyl isomerase/rotomase, Frp1 (5,6), protein kinase Tap42 (7)(8)(9)(10)(11)(12)(13)(14)46), Tip41 (11,15), type 2A protein phosphatases, Pph21/22 (8,14), Sit4 (7, 8, 14, 16 -18), Pph3 (16), Sit4-associated proteins or SAPS (11,17,19,20), Lst8, which participates in protein trafficking (21)(22)(23), and proteins found in complexes with Tor1/2, Kog1, Avo1-3, Tco89, and Bit6 (21,22).…”

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confidence: 99%

Methionine Sulfoximine Treatment and Carbon Starvation Elicit Snf1-independent Phosphorylation of the Transcription Activator Gln3 in Saccharomyces cerevisiae

Tate

Rai

Cooper

2005

Journal of Biological Chemistry

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Tor proteins are global regulators situated at the top of a signal transduction pathway conserved from yeast to humans. Specific inhibition of the two Saccharomyces cerevisiae Tor proteins by rapamycin alters many cellular processes and the expression of hundreds of genes. Among the regulated genes are those whose expression is activated by the GATA family transcription activator, Gln3. The extent of Gln3 phosphorylation has been thought to determine its intracellular localization, with phosphorylated and dephosphorylated forms accumulating in the cytoplasm and nucleus, respectively. Data presented here demonstrate that rapamycin and the glutamine synthetase inhibitor, methionine sulfoximine (MSX), although eliciting the same outcomes with respect to Gln3-Myc 13 nuclear accumulation and nitrogen catabolite repression-sensitive transcription, generate diametrically opposite effects on Gln3-Myc 13 phosphorylation. MSX increases Gln3-Myc 13 phosphorylation and rapamycin decreases it. Gln3-Myc 13 phosphorylation levels are regulated by at least three mechanisms as follows: (i) depends on Snf1 kinase as observed during carbon starvation, (ii) is Snf1-independent as observed during both carbon starvation and MSX treatment, and (iii) is rapamycin-induced dephosphorylation. MSX and rapamycin act additively on Gln3-Myc 13 phosphorylation, but MSX clearly predominates. These results suggest that MSX-and rapamycin-inhibited proteins are more likely to function in separate regulatory pathways than they are to function tandemly in a single pathway as thought previously. Furthermore, as we and others have detected thus far, Gln3 phosphorylation/dephosphorylation is not a demonstrably required step in achieving Gln3 nuclear localization and nitrogen catabolite repression-sensitive transcription in response to MSX or rapamycin treatment.

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“…The prevailing model posits that active Tor1/2 phosphorylate Tap42 and Tip41 which, in a way not fully understood, results in inactivation of Sit4, one of two phosphoprotein phosphatases suggested to be responsible for Gln3 dephosphorylation (10,13,17,18). Tor1/2 are also suggested by some investigators to be the kinases responsible for Gln3 phosphorylation itself (13,16).…”

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confidence: 99%

Gln3 Phosphorylation and Intracellular Localization in Nutrient Limitation and Starvation Differ from Those Generated by Rapamycin Inhibition of Tor1/2 in Saccharomyces cerevisiae

Cox

Kulkarni

Tate

et al. 2004

Journal of Biological Chemistry

101

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The ability of the cell to sense environmental conditions and alter gene expression in response to them is critical to its survival. In Saccharomyces cerevisiae, the Tor1/2 serine/threonine kinases are global regulators situated at the top of a signal cascade reported to receive and transmit nutritional signals associated with the nitrogen supply of the cell. At the other end of that cascade is Gln3, one of two transcriptional activators responsible for most nitrogen catabolic gene expression. When nitrogen is in excess, Tor1/2 are active, and Gln3 is phosphorylated and localizes to the cytoplasm. If Tor1/2 are inhibited by rapamycin or mutation, Gln3 becomes dephosphorylated, accumulates in the nucleus, and mediates nitrogen catabolite repression (NCR)-sensitive transcription. The observations that Gln3 also accumulates in the nuclei of cells provided with poor nitrogen sources or during nitrogen starvation has led to the conclusion that Tor1/2 control intracellular Gln3 localization and NCR-sensitive transcription by regulating Gln3 phosphorylation/dephosphorylation. To test this model, we compared Gln3 phosphorylation states and intracellular localizations under a variety of physiological conditions known to elicit different levels of NCRsensitive transcription. Our data indicate that: (i) observable Gln3 phosphorylation levels do not correlate in a consistent way with the quality or quantity of the nitrogen source provided, the intracellular localization of Gln3, or the capacity to support NCR-sensitive transcription. (ii) Gln3-Myc 13 is hyperphosphorylated during nitrogen and carbon starvation, but this uniform response does not correlate with Gln3 intracellular localization. (iii) Gln3-Myc 13 dephosphorylation and nuclear localization correlate with one another at early but not late times after rapamycin treatment. These data suggest that rapamycin treatment and growth with poor nitrogen sources bring about nuclear accumulation of Gln3 but likely do so by different mechanisms or by a common mechanism involving molecules other than Gln3 and/or other than the levels of Gln3-Myc 13 phosphorylation thus far detected by others and ourselves.

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TIP41 Interacts with TAP42 and Negatively Regulates the TOR Signaling Pathway

Cited by 219 publications

References 28 publications

A Novel, Evolutionarily Conserved Protein Phosphatase Complex Involved in Cisplatin Sensitivity

A Novel, Evolutionarily Conserved Protein Phosphatase Complex Involved in Cisplatin Sensitivity

Methionine Sulfoximine Treatment and Carbon Starvation Elicit Snf1-independent Phosphorylation of the Transcription Activator Gln3 in Saccharomyces cerevisiae

Gln3 Phosphorylation and Intracellular Localization in Nutrient Limitation and Starvation Differ from Those Generated by Rapamycin Inhibition of Tor1/2 in Saccharomyces cerevisiae

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