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Cited by 95Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

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

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Ugi, Satoshi, Imamura, Takeshi, Ricketts, William, Olefsky, Jerrold M.·2002·Molecular and Cellular Biology
DOI 10.1128/mcb.22.7.2375-2387.2002PMC PMC133677
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Abstract

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.

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  • PP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, MEK, ERK, and Akt.

    “Furthermore, PP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Akt (Dennis et al., 2014; Junttila et al., 2007; Ugi et al., 2002).”

    From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Ugi et al., 2002

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Authors
Ugi, S., Imamura, T., Ricketts, W., & Olefsky, J. M.
Affiliations
Veterans Health Administration (US)
Corresponding author
Olefsky, Jerrold M.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2002-04-01
Volume
22
Issue
7
Pages
2375-2387
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.22.7.2375-2387.2002
PMC
PMC133677
OpenAlex
W2119741242
Cited by
95
References
59
Citations by year
2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 3
FWCI
3.13
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-33651, R37DK033651, R01DK033651)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
protein phosphatase 2A, Shc, tyrosine phosphorylation, RAS/MAPK pathway, small T antigen, PP2A regulatory subunit, phosphotyrosine binding domain, Grb2, MEK, Raf-1, insulin signaling, epidermal growth factor, insulin-like growth factor I, protein phosphatase 1, mitogenic signaling
MeSH terms
Animals, Antigens, Viral, Tumor, Cell Line, DNA, Epidermal Growth Factor, Humans, Insulin, Insulin-Like Growth Factor I, Mitogens, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Proteins, Swine, Signal Transduction, Protein Structure, Tertiary, Phosphotyrosine, Intramolecular Transferases, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinases, Macromolecular Substances, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Rats, Protein Phosphatase 1, Protein Phosphatase 2

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