title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kin Man
authors.initials: KM
authors.lastname: Suen
authors.forename: Chi-Chuan
authors.initials: CC
authors.lastname: Lin
authors.forename: Roger
authors.initials: R
authors.lastname: George
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Melo
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Biggs
authors.forename: Zamal
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Drake
authors.forename: Swathi
authors.initials: S
authors.lastname: Arur
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1