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:14724641

From GONUTS
Jump to: navigation, search
Citation

Matheny, SA, Chen, C, Kortum, RL, Razidlo, GL, Lewis, RE and White, MA (2004) Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427:256-60

Abstract

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.

Links

PubMed Online version:10.1038/nature02237

Keywords

Animals; Cell Line; Enzyme Activation; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases/metabolism; Molecular Sequence Data; Protein Binding; Protein Kinases/genetics; Protein Kinases/metabolism; Proto-Oncogene Proteins c-raf/metabolism; Rats; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/chemistry; Ubiquitin-Protein Ligases/metabolism; Xenopus Proteins/chemistry; Xenopus Proteins/metabolism; Xenopus laevis; ras Proteins/metabolism

Significance

Annotations

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

HUMAN:RASH

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7Z569

F

Seeded From UniProt

complete

HUMAN:BRAP

involved_in

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRAP

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7Z569

F

Seeded From UniProt

complete

HUMAN:BRAP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P01112

F

Seeded From UniProt

complete

HUMAN:BRAP

involved_in

GO:0009968: negative regulation of signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRAP

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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