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PMID:11585837

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Citation

Gross, I, Bassit, B, Benezra, M and Licht, JD (2001) Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J. Biol. Chem. 276:46460-8

Abstract

Sprouty was genetically identified as an antagonist of fibroblast growth factor signaling during tracheal branching in Drosophila. In this study, we provide a functional characterization of mammalian Sprouty1 and Sprouty2. Sprouty1 and Sprouty2 inhibited events downstream of multiple receptor tyrosine kinases and regulated both cell proliferation and differentiation. Using NIH3T3 cell lines conditionally expressing Sprouty1 or Sprouty2, we found that these proteins specifically inhibit the Ras/Raf/MAP kinase pathway by preventing Ras activation. In contrast, activation of the phosphatidylinositol 3-kinase pathway was not affected by Sprouty1 or Sprouty2. We further showed that Sprouty1 and Sprouty2 do no prevent the formation of a SNT.Grb2.Sos complex upon fibroblast growth factor stimulation, yet block Ras activation. Taken together, these results establish mammalian Sprouty proteins as important negative regulators of growth factor signaling and suggest that Sprouty proteins act downstream of the Grb2.Sos complex to selectively uncouple growth factor signals from Ras activation and the MAP Kinase pathway.

Links

PubMed Online version:10.1074/jbc.M108234200

Keywords

3T3 Cells; Animals; Blotting, Western; Cell Differentiation/physiology; Cell Division/physiology; MAP Kinase Signaling System; Membrane Proteins/physiology; Mice; Nerve Tissue Proteins/physiology; PC12 Cells; Phosphoproteins/physiology; Precipitin Tests; Rats; ras Proteins/antagonists & inhibitors; ras Proteins/metabolism

Significance

Annotations

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

MOUSE:GRB2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9QXV8

F

Seeded From UniProt

complete

MOUSE:SPY2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q60631

F

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0034260: negative regulation of GTPase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0051387: negative regulation of neurotrophin TRK receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0046580: negative regulation of Ras protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY2

acts_upstream_of_or_within

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0034260: negative regulation of GTPase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0051387: negative regulation of neurotrophin TRK receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0046580: negative regulation of Ras protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPY1

acts_upstream_of_or_within

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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