ArticleOncogene2000
Constitutive activation of the Ras/MAP kinase pathway and enhanced TCR signaling by targeting the Shc adaptor to membrane rafts.
Article in Oncogene, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 53 citations in OpenAlex.
- Oligomer-dependent and oligomer-independent pathogenesis of muscular dystrophy-associated mutations within the penta-EF-hand domain of calpain-3.The Journal of biological chemistry · 2026Article
- Current understanding of CTLA-4: from mechanism to autoimmune diseases.Frontiers in immunology · 2023Review
- p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB.Frontiers in oncology · 2022Article
- A Link Between Alzheimer's and Type II Diabetes Mellitus? CaBioEssays : news and reviews in molecular, cellular and developmental biology · 2018Review
- Lipid raft redox signaling: molecular mechanisms in health and disease.Antioxidants & redox signaling · 2011Review
- Molecular dynamics simulations reveal that Tyr-317 phosphorylation reduces Shc binding affinity for phosphotyrosyl residues of epidermal growth factor receptor.Biophysical journal · 2009Article
- p66shc negatively regulates insulin-like growth factor I signal transduction via inhibition of p52shc binding to Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 leading to impaired growth factor receptor-bound protein-2 membrane recruitment.Molecular endocrinology (Baltimore, Md.) · 2008Article
- Lipid rafts and caveolae in signaling by growth factor receptors.The open biochemistry journal · 2007Article
- ShcA mediates the dominant pathway to extracellular signal-regulated kinase activation during early thymic development.Molecular and cellular biology · 2006Article
- Article
- p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells.Molecular and cellular biology · 2004Article
- Extensive temporally regulated reorganization of the lipid raft proteome following T-cell antigen receptor triggering.The Biochemical journal · 2003Article
- Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression.Proceedings of the National Academy of Sciences of the United States of America · 2002Article
- Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions.Oncogene · 2001Article
- Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.Molecular and cellular biology · 2001Article
- EMBO WORKSHOP REPORT: lymphocyte antigen receptor and coreceptor signaling Siena, Italy, November 6-10, 1999.The EMBO journal · 2000Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The Shc adaptor is responsible for coupling receptor tyrosine kinases and tyrosine kinase-associated receptors to the Ras/MAP kinase pathway. Shc is believed to be regulated by a change in subcellular localization from the cytosol to the plasma membrane, where it recruits Grb-2/Sos complexes and hence permits juxtaposition of the guanine nucleotide exchange factor Sos to Ras, resulting in GDP/GTP exchange and Ras activation. Shc has been recently shown to inducibly colocalize in detergent-resistant membrane rafts together with the activated TCR and associated signaling molecules. To understand whether Shc localization in membrane rafts is sufficient to regulate Shc function, we constructed a Shc chimera containing the Ras membrane localization motif at the C-terminus. We show that membrane targeted Shc was constitutively localized in the plasma membrane of T-cells, and was mostly compartmentalized in lipid rafts. Membrane targeted Shc was phosphorylated on tyrosine residues and bound Grb-2/Sos in the absence of TCR engagement. Furthermore, expression of membrane targeted Shc resulted in constitutive downstream signaling, including Erk2 activation and enhancement of TCR dependent activation of the TCR responsive transcription factor NF-AT. Hence localization of Shc in membrane rafts is sufficient for Shc to acquire a signaling competent state. Interestingly, a membrane targeted Shc mutant lacking both Grb-2 binding sites was not only incapable of signaling in the absence of TCR triggering, but transdominantly inhibited endogenous Shc, supporting a non redundant role for Shc in the activation of the Ras/MAP kinase pathway in T-cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.