Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling.


:Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase that carries out multiple functions. Although numerous observations suggest that PP2A plays a major role in downregulation of the mitogen-activated protein (MAP) kinase pathway, the precise mechanisms are unknown. To clarify the role of PP2A in growth factor (insulin, epidermal growth factor [EGF], and insulin-like growth factor 1 [IGF-1]) stimulation of the Ras/MAP kinase pathway, simian virus 40 small t antigen was expressed in Rat-1 fibroblasts which overexpress insulin receptors. Small t antigen is known to specifically inhibit PP2A by binding to the A PP2A regulatory subunit, interfering with the ability of PP2A to bind to its cellular substrates. Overexpressed small t protein was coimmunoprecipitated with PP2A and inhibited cellular PP2A activity but did not inhibit protein phosphatase 1 (PP1) activity. Insulin, IGF-1, and EGF stimulation also inhibited PP2A activity. Growth factor-stimulated Ras, Raf-1, MAP kinase, and mitogen-activated extracellular-signal-regulated kinase kinase (MEK) activities were elevated in small-t-antigen-expressing cells. Furthermore, Shc tyrosine phosphorylation and its association with Grb2 were also elevated in small-t-antigen-expressing cells. Expression levels of Shc, Ras, MEK, or MAP kinase and phosphorylation of insulin, EGF, and IGF-1 receptors were not altered. Interestingly, we found that PP2A associated with Shc in the basal state and dissociated in response to insulin and EGF and that this dissociation was inhibited by 65% in small-t-antigen-expressing cells. In addition, we found that PP2A associates with the phosphotyrosine-binding domain (PTB domain) of Shc and that phosphorylation of tyrosine 317 of Shc was required for PP2A-Shc dissociation. We conclude (i) that PP2A negatively regulates the Ras/MAP kinase pathway by binding to Shc, inhibiting tyrosine phosphorylation; (ii) that the Shc-PP2A association is mediated by the Shc PTB domain but the interaction is independent of phosphotyrosine binding, indicating a new molecular function for the PTB domain; (iii) that growth factor stimulation, or small-t-antigen expression, causes dissociation of the PP2A-Shc complex, facilitating Shc phosphorylation and downstream activations of the Ras/MAP kinase pathway; and (iv) that this defines a new mechanism of small-t-antigen action to promote mitogenesis.


Mol Cell Biol


Ugi S,Imamura T,Ricketts W,Olefsky JM




Has Abstract


2002-04-01 00:00:00












  • Kinase-independent functions of TEL1 in telomere maintenance.

    abstract::TEL1 is important in Saccharomyces cerevisiae telomere maintenance, and its kinase activity is required. Tel1p associates with telomeres in vivo, is enriched at short telomeres, and enhances the binding of telomerase components to short telomeres. However, it is unclear how the kinase activity and telomere association...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Ma Y,Greider CW

    更新日期:2009-09-01 00:00:00

  • Active-site mutations in the Xrn1p exoribonuclease of Saccharomyces cerevisiae reveal a specific role in meiosis.

    abstract::Xrn1p of Saccharomyces cerevisiae is a major cytoplasmic RNA turnover exonuclease which is evolutionarily conserved from yeasts to mammals. Deletion of the XRN1 gene causes pleiotropic phenotypes, which have been interpreted as indirect consequences of the RNA turnover defect. By sequence comparisons, we have identifi...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Solinger JA,Pascolini D,Heyer WD

    更新日期:1999-09-01 00:00:00

  • Two-level regulation of cardiac actin gene transcription: muscle-specific modulating factors can accumulate before gene activation.

    abstract::We have previously proposed that the upstream regions of the human cardiac actin gene contain sequences that interact with muscle-specific factors with direct high-level transcription of this gene in differentiated muscle cells. In this study we showed that these factors already accumulate in the dividing myoblasts of...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Minty A,Blau H,Kedes L

    更新日期:1986-06-01 00:00:00

  • Essential roles of Bdp1, a subunit of RNA polymerase III initiation factor TFIIIB, in transcription and tRNA processing.

    abstract::The essential Saccharomyces cerevisiae gene BDP1 encodes a subunit of RNA polymerase III (Pol III) transcription factor (TFIIIB); TATA box binding protein (TBP) and Brf1 are the other subunits of this three-protein complex. Deletion analysis defined three segments of Bdp1 that are essential for viability. A central se...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Ishiguro A,Kassavetis GA,Geiduschek EP

    更新日期:2002-05-01 00:00:00

  • Kinds and spectrum of mutations induced by 1-nitrosopyrene adducts during plasmid replication in human cells.

    abstract::1-Nitropyrene has been shown in bacterial assays to be the principal mutagenic agent in diesel emission particulates. It has also been shown to be mutagenic in human fibroblasts and carcinogenic in animals. To investigate the kinds of mutations induced by this carcinogen and compare them with those induced by a struct...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Yang JL,Maher VM,McCormick JJ

    更新日期:1988-08-01 00:00:00

  • Poly(A)-binding protein-interacting protein 1 binds to eukaryotic translation initiation factor 3 to stimulate translation.

    abstract::Poly(A)-binding protein (PABP) stimulates translation initiation by binding simultaneously to the mRNA poly(A) tail and eukaryotic translation initiation factor 4G (eIF4G). PABP activity is regulated by PABP-interacting (Paip) proteins. Paip1 binds PABP and stimulates translation by an unknown mechanism. Here, we desc...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Martineau Y,Derry MC,Wang X,Yanagiya A,Berlanga JJ,Shyu AB,Imataka H,Gehring K,Sonenberg N

    更新日期:2008-11-01 00:00:00

  • Modulation of transcriptional activation of the proliferating cell nuclear antigen promoter by the adenovirus E1A 243-residue oncoprotein depends on proximal activators.

    abstract::Previous analyses defined a proliferating cell nuclear antigen (PCNA) E1A-responsive element (PERE) in the PCNA promoter that is essential for transactivation by the 243-residue product of the adenovirus type 2 E1A 12S mRNA (E1A 243R). In this report, we show that the PERE activates a heterologous basal promoter and c...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Morris GF,Labrie C,Mathews MB

    更新日期:1994-01-01 00:00:00

  • Function of the MYND Domain and C-Terminal Region in Regulating the Subcellular Localization and Catalytic Activity of the SMYD Family Lysine Methyltransferase Set5.

    abstract::SMYD lysine methyltransferases target histones and nonhistone proteins for methylation and are critical regulators of muscle development and implicated in neoplastic transformation. They are characterized by a split catalytic SET domain and an intervening MYND zinc finger domain, as well as an extended C-terminal doma...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Jaiswal D,Turniansky R,Moresco JJ,Ikram S,Ramaprasad G,Akinwole A,Wolf J,Yates JR 3rd,Green EM

    更新日期:2020-01-03 00:00:00

  • Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation.

    abstract::Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1alpha and HIF2alpha, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIFalpha and HIFbeta (ARNT) subunits. Placentas from...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cowden Dahl KD,Fryer BH,Mack FA,Compernolle V,Maltepe E,Adelman DM,Carmeliet P,Simon MC

    更新日期:2005-12-01 00:00:00

  • Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice.

    abstract::Muscle creatine kinase (MCK) is expressed at high levels only in skeletal and cardiac muscle tissues. Previous in vitro transfection studies of skeletal muscle myoblasts and fibroblasts had identified two MCK enhancer elements and one proximal promoter element, each of which exhibited expression only in differentiated...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Johnson JE,Wold BJ,Hauschka SD

    更新日期:1989-08-01 00:00:00

  • Repair of specific base pair mismatches formed during meiotic recombination in the yeast Saccharomyces cerevisiae.

    abstract::Heteroduplexes formed between DNA strands derived from different homologous chromosomes are an intermediate in meiotic crossing over in the yeast Saccharomyces cerevisiae and other eucaryotes. A heteroduplex formed between wild-type and mutant genes will contain a base pair mismatch; failure to repair this mismatch wi...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Detloff P,Sieber J,Petes TD

    更新日期:1991-02-01 00:00:00

  • Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation.

    abstract::The nuclear receptor peroxisome proliferator-activated receptor gamma regulates adipose differentiation and systemic insulin signaling via ligand-dependent transcriptional activation of target genes. However, the identities of the biologically relevant target genes are largely unknown. Here we describe the isolation a...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Yoon JC,Chickering TW,Rosen ED,Dussault B,Qin Y,Soukas A,Friedman JM,Holmes WE,Spiegelman BM

    更新日期:2000-07-01 00:00:00

  • Differential DNA binding by monomeric, homodimeric, and potentially heteromeric forms of the thyroid hormone receptor.

    abstract::Binding of the thyroid hormone receptor (TR) to thyroid hormone-responsive elements (TREs) is crucial for regulation of gene expression by thyroid hormone. The TR binds to each half-site of a palindromic TRE separately, as a monomer, or simultaneously, as a homodimer. In addition, the TR monomer interacts with a 42-kD...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Lazar MA,Berrodin TJ,Harding HP

    更新日期:1991-10-01 00:00:00

  • Functional organization of the simian virus 40 origin of DNA replication.

    abstract::To define the sequence elements involved in initiation of DNA synthesis at the simian virus 40 origin of replication, we determined the relative replication efficiencies in vitro and in vivo of templates containing a variety of mutations within the origin region. Replication of the mutants in vitro was assayed by the ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Li JJ,Peden KW,Dixon RA,Kelly T

    更新日期:1986-04-01 00:00:00

  • Poly(A) tail length control in Saccharomyces cerevisiae occurs by message-specific deadenylation.

    abstract::We report that newly synthesized mRNA poly(A) tails are matured to precise lengths by the Pab1p-dependent poly(A) nuclease (PAN) of Saccharomyces cerevisiae. These results provide evidence for an initial phase of mRNA deadenylation that is required for poly(A) tail length control. In RNA 3'-end processing extracts lac...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Brown CE,Sachs AB

    更新日期:1998-11-01 00:00:00

  • Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex.

    abstract::BCS1, a component of the inner membrane of mitochondria, belongs to the group of proteins with internal, noncleavable import signals. Import and intramitochondrial sorting of BCS1 are encoded in the N-terminal 126 amino acid residues. Three sequence elements were identified in this region, namely, the transmembrane do...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Stan T,Brix J,Schneider-Mergener J,Pfanner N,Neupert W,Rapaport D

    更新日期:2003-04-01 00:00:00

  • 1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol Attenuates Streptozotocin-Induced Pancreatic Beta Cell Damage by Promoting Glucose Transporter 2 Endocytosis.

    abstract::Streptozotocin (STZ) is widely used to induce diabetic rodent models. It is specifically toxic to pancreatic beta cells and causes severe destruction and dysfunction. We investigated the effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on an STZ-induced diabetic mouse model. PLAG attenuated the glucose i...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kim J,Kim JH,Sohn KY,Yoon SY,Kim JW

    更新日期:2019-10-11 00:00:00

  • Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.

    abstract::Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FG...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Goetz R,Beenken A,Ibrahimi OA,Kalinina J,Olsen SK,Eliseenkova AV,Xu C,Neubert TA,Zhang F,Linhardt RJ,Yu X,White KE,Inagaki T,Kliewer SA,Yamamoto M,Kurosu H,Ogawa Y,Kuro-o M,Lanske B,Razzaque MS,Mohammadi M

    更新日期:2007-05-01 00:00:00

  • Detection of deletion mutations in pSV2gpt-transformed cells.

    abstract::We have developed a system to study mutations that affect xanthine-guanine phosphoribosyltransferase gene (gpt) expression in hypoxanthine-guanine phosphoribosyltransferase-deficient CHO cells that have been transformed by the plasmid vector pSV2gpt. One isolated transformant, designated AS52, carries a single copy of...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Tindall KR,Stankowski LF Jr,Machanoff R,Hsie AW

    更新日期:1984-07-01 00:00:00

  • DNA cleavage activity of the V(D)J recombination protein RAG1 is autoregulated.

    abstract::RAG1 and RAG2 catalyze the first DNA cleavage steps in V(D)J recombination. We demonstrate that the isolated central domain of RAG1 has inherent single-stranded (ss) DNA cleavage activity, which does not require, but is enhanced by, RAG2. The central domain, therefore, contains the active-site residues necessary to pe...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: De P,Peak MM,Rodgers KK

    更新日期:2004-08-01 00:00:00

  • Roles of hnRNP A1, SR proteins, and p68 helicase in c-H-ras alternative splicing regulation.

    abstract::Human ras genes play central roles in coupling extracellular signals with complex intracellular networks controlling proliferation, differentiation, and apoptosis, among others processes. c-H-ras pre-mRNA can be alternatively processed into two mRNAs due to the inclusion or exclusion of the alternative exon IDX; this ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Guil S,Gattoni R,Carrascal M,Abián J,Stévenin J,Bach-Elias M

    更新日期:2003-04-01 00:00:00

  • Activation domains of L-Myc and c-Myc determine their transforming potencies in rat embryo cells.

    abstract::Members of the Myc family of proteins share a number of protein motifs that are found in regulators of gene transcription. Conserved stretches of amino acids found in the N-terminal transcriptional activation domain of c-Myc are required for cotransforming activity. Most of the Myc proteins contain the basic helix-loo...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Barrett J,Birrer MJ,Kato GJ,Dosaka-Akita H,Dang CV

    更新日期:1992-07-01 00:00:00

  • DNA-binding activities of the Drosophila melanogaster even-skipped protein are mediated by its homeo domain and influenced by protein context.

    abstract::The homeo box gene even-skipped (eve) encodes a 376-amino-acid protein that binds with high affinity to sequences located near the 5' termini of the eve and en genes. The 5' en sites are A + T rich and contain copies of the 10-base-pair (bp) consensus sequence T-C-A-A-T-T-A-A-A-T. In contrast, the 5' eve sites are G +...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hoey T,Warrior R,Manak J,Levine M

    更新日期:1988-11-01 00:00:00

  • Telomerase- and Rad52-independent immortalization of budding yeast by an inherited-long-telomere pathway of telomeric repeat amplification.

    abstract::In the absence of telomerase, telomeres erode, provoking accumulation of DNA damage and death by senescence. Rare survivors arise, however, due to Rad52-based amplification of telomeric sequences by homologous recombination. The present study reveals that in budding yeast cells, postsenescence survival relying on ampl...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Grandin N,Charbonneau M

    更新日期:2009-02-01 00:00:00

  • Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation.

    abstract::The inducible transcriptional complex AP-1, composed of c-Fos and c-Jun proteins, is crucial for cell adaptation to many environmental changes. While its mechanisms of activation have been extensively studied, how its activity is restrained is poorly understood. We report here that lysine 265 of c-Fos is conjugated by...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bossis G,Malnou CE,Farras R,Andermarcher E,Hipskind R,Rodriguez M,Schmidt D,Muller S,Jariel-Encontre I,Piechaczyk M

    更新日期:2005-08-01 00:00:00

  • Association of Rad9 with double-strand breaks through a Mec1-dependent mechanism.

    abstract::Rad9 is required for the activation of DNA damage checkpoint pathways in budding yeast. Rad9 is phosphorylated after DNA damage in a Mec1- and Tel1-dependent manner and subsequently interacts with Rad53. This Rad9-Rad53 interaction has been suggested to trigger the activation and phosphorylation of Rad53. Here we show...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Naiki T,Wakayama T,Nakada D,Matsumoto K,Sugimoto K

    更新日期:2004-04-01 00:00:00

  • Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.

    abstract::Lipophilic compounds such as retinoic acid and long-chain fatty acids regulate gene transcription by activating nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). These compounds also bind in cells to members of the family of intracellular lipid binding pr...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Tan NS,Shaw NS,Vinckenbosch N,Liu P,Yasmin R,Desvergne B,Wahli W,Noy N

    更新日期:2002-07-01 00:00:00

  • Cell-specific expression of the human parathyroid hormone gene in rat pituitary cells.

    abstract::The promoter region of the human parathyroid hormone gene was fused to the Escherichia coli neo gene and introduced into GH4C1 rat pituitary and human HeLa cells. Both TATA boxes of the human parathyroid hormone gene accurately directed transcription in GH4C1 cells; the parathyroid hormone promoter was inactive in HeL...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Igarashi T,Okazaki T,Potter H,Gaz R,Kronenberg HM

    更新日期:1986-05-01 00:00:00

  • The role and fate of DNA ends for homologous recombination in embryonic stem cells.

    abstract::We have analyzed the gene-targeting frequencies and recombination products generated by a series of vectors which target the hprt locus in embryonic stem cells and found the existence of alternative pathways that depend on the location of the double-strand break within the vector. A double-strand break in the targetin...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hasty P,Rivera-Pérez J,Bradley A

    更新日期:1992-06-01 00:00:00

  • Characterization of reaper- and FADD-induced apoptosis in a lepidopteran cell line.

    abstract::Expression of the reaper gene (rpr) correlates with the initiation of apoptosis in Drosophila melanogaster. Transient expression of rpr in the lepidopteran SF-21 cell line induced apoptosis displaying nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body f...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Vucic D,Seshagiri S,Miller LK

    更新日期:1997-02-01 00:00:00