GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:11884620

From GONUTS
Jump to: navigation, search
Citation

Ugi, S, Imamura, T, Ricketts, W and Olefsky, JM (2002) Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. Mol. Cell. Biol. 22:2375-87

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.

Links

PubMed PMC133677

Keywords

Adaptor Proteins, Signal Transducing; Animals; Antigens, Viral, Tumor/genetics; Antigens, Viral, Tumor/metabolism; Cell Line; DNA/biosynthesis; Epidermal Growth Factor/pharmacology; GRB2 Adaptor Protein; Humans; Insulin/pharmacology; Insulin-Like Growth Factor I/pharmacology; Intramolecular Transferases/chemistry; Intramolecular Transferases/metabolism; Macromolecular Substances; Mitogen-Activated Protein Kinases/metabolism; Mitogens/pharmacology; Phosphoprotein Phosphatases/metabolism; Phosphorylation/drug effects; Phosphotyrosine/metabolism; Protein Binding/drug effects; Protein Phosphatase 1; Protein Phosphatase 2; Protein Structure, Tertiary; Proteins/metabolism; Proto-Oncogene Proteins c-raf/metabolism; Rats; Signal Transduction/drug effects; Swine

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:PP2AB

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:PP2AB

involved_in

GO:0046580: negative regulation of Ras protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PP2AA

enables

GO:0019904: protein domain specific binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:PP2AA

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PP2AA

enables

GO:0043422: protein kinase B binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:2081

F

Seeded From UniProt

complete

RAT:PP2AA

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:620446

F

Seeded From UniProt

complete

RAT:PP2AA

enables

GO:0051721: protein phosphatase 2A binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:SHC1

enables

GO:0051721: protein phosphatase 2A binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3380

F

Seeded From UniProt

complete

RAT:SHC1

enables

GO:0051721: protein phosphatase 2A binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:SHC1

involved_in

GO:0032869: cellular response to insulin stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SHC1

enables

GO:0044877: protein-containing complex binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3380

F

Seeded From UniProt

complete

RAT:AKT1

enables

GO:0051721: protein phosphatase 2A binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3380

F

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.