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Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli.

ABSTRACT: Control mechanisms that prevent aberrant signaling are necessary to maintain cellular homeostasis. We describe a new mechanism by which the adaptor protein Shc directly binds the MAP kinase Erk, thus preventing its activation in the absence of extracellular stimuli. The Shc-Erk complex restricts Erk nuclear translocation, restraining Erk-dependent transcription of genes, including those responsible for oncogenic growth. The complex forms through unique binding sites on both the Shc PTB domain and the N-terminal lobe of Erk. Upon receptor tyrosine kinase stimulation, a conformational change within Shc-induced through interaction with the phosphorylated receptor-releases Erk, allowing it to fulfill its role in signaling. Thus, in addition to its established role in promoting MAP kinase signaling in stimulated cells, Shc negatively regulates Erk activation in the absence of growth factors and thus could be considered a tumor suppressor in human cells.

SUBMITTER: Suen KM

PROVIDER: S-EPMC4059177 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli.

Suen Kin Man KM Lin Chi-Chuan CC George Roger R Melo Fernando A FA Biggs Eleanor R ER Ahmed Zamal Z Drake Melanie N MN Arur Swathi S Arold Stefan T ST Ladbury John E JE

Nature structural & molecular biology 20130414 5

Control mechanisms that prevent aberrant signaling are necessary to maintain cellular homeostasis. We describe a new mechanism by which the adaptor protein Shc directly binds the MAP kinase Erk, thus preventing its activation in the absence of extracellular stimuli. The Shc-Erk complex restricts Erk nuclear translocation, restraining Erk-dependent transcription of genes, including those responsible for oncogenic growth. The complex forms through unique binding sites on both the Shc PTB domain an ...[more]

PMID: 23584453

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Project description:BackgroundFatal neurodegenerative disorders such as Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases in humans, scrapie and bovine spongiform encephalopathy in animals, are characterized by the accumulation in the brain of a pathological form of the prion protein (PrP) denominated PrPSc. The latter derives from the host cellular form, PrPC, through a process whereby portions of its alpha-helical and coil structures are refolded into beta-sheet structures.ResultsIn this work, the widely known in vitro model of prion replication, hypothalamic GT1-1 cell line, was used to investigate cellular and molecular responses to prion infection. The MAP kinase cascade was dissected to assess the phosphorylation levels of src, MEK 1/2 and ERK 1/2 signaling molecules, both before and after prion infection. Our findings suggest that prion replication leads to a hyper-activation of this pathway. Biochemical analysis was complemented with immunofluorescence studies to map the localization of the ERK complex within the different cellular compartments. We showed how the ERK complex relocates in the cytosol upon prion infection. We correlated these findings with an impairment of cell growth in prion-infected GT1-1 cells as probed by MTT assay. Furthermore, given the persistent urgency in finding compounds able to cure prion infected cells, we tested the effects on the ERK cascade of two molecules known to block prion replication in vitro, quinacrine and Fab D18. We were able to show that while these two compounds possess similar effects in curing prion infection, they affect the MAP kinase cascade differently.ConclusionsTaken together, our results help shed light on the molecular events involved in neurodegeneration and neuronal loss in prion infection and replication. In particular, the combination of chronic activation and aberrant localization of the ERK complex may lead to a lack of essential neuroprotective and survival factors. Interestingly, these data seem to define some common traits with other neurodegenerative disorders such as, for example, Alzheimer's disease.

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Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli.

Publications

Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli.

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