Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli
George, Roger R.
Melo, Fernando A.
Biggs, Eleanor R.
Drake, Melanie N.
Arold, Stefan T.
Ladbury, John E S D
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/562754
MetadataShow full item record
AbstractControl 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. © 2013 Nature America, Inc. All rights reserved.
PublisherNature Publishing Group
- Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events.
- Authors: Schlaepfer DD, Jones KC, Hunter T
- Issue date: 1998 May
- The src homology 2 and phosphotyrosine binding domains of the ShcC adaptor protein function as inhibitors of mitogenic signaling by the epidermal growth factor receptor.
- Authors: O'Bryan JP, Lambert QT, Der CJ
- Issue date: 1998 Aug 7
- Discrimination between phosphotyrosine-mediated signaling properties of conventional and neuronal Shc adapter molecules.
- Authors: Nakamura T, Komiya M, Gotoh N, Koizumi S, Shibuya M, Mori N
- Issue date: 2002 Jan 3
- Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line.
- Authors: Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, Kanda Y, Nishio Y, Jikihara H, Matsuura N, Murata Y
- Issue date: 1999 Oct 15
- Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase.
- Authors: Besset V, Scott RP, Ibáñez CF
- Issue date: 2000 Dec 15