Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Sehar Saleem
  • Firdous A. KhandayEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101504


Historical Background

The Shc family of proteins consists four members, ShcA, ShcB, ShcC, and ShcD, of which the best characterized to date is ShcA (Rozakis-Adcock et al. 1992). ShcA, or simply Shc, was identified in 1992 as an adaptor protein which linked the activated EGFR (epidermal growth factor receptor) to Ras and the MAP (mitogen-activated protein) kinase cascade (Ravichandran 2001). Shc is expressed as three isoforms which have the molecular weights of 66, 52, and 46 kDa, respectively. These isoforms are designated according to their molecular weight. p66Shc is the longest isoform of the three and also consists of the collagen homology domain (CH2), which is unique to it.

P66Shc Structure

All proteins of the Shc family share a unique and highly conserved domain organization, having an N-terminal PTB domain and a C-terminal SH2 domain. Collagen homology (CH1) is proline-rich central domain...
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  1. Arany I, Faisal A, Nagamine Y, Safirstein RL. p66shc inhibits pro-survival epidermal growth factor receptor/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells. J Biol Chem. 2008;283:6110–7.CrossRefPubMedGoogle Scholar
  2. Galimov ER, Chernyak BV, Sidorenko AS, Tereshkova AV, Chumakov PM. Prooxidant properties of p66shc are mediated by mitochondria in human cells. PLoS One. 2014;9:e86521.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Gotoh N, Tojo A, Shibuya M. A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3. EMBO J. 1996;15:6197.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Innocenti M, Tenca P, Frittoli E, Faretta M, Tocchetti A, Di Fiore PP, et al. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J Cell Biol. 2002;156:125–36.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Khanday FA, Yamamori T, Mattagajasingh I, Zhang Z, Bugayenko A, Naqvi A, et al. Rac1 leads to phosphorylation-dependent increase in stability of the p66shc adaptor protein: role in Rac1-induced oxidative stress. Mol Biol Cell. 2006;17:122–9.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KMV, Superti-Furga G, et al. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor–MAP kinase–fos signalling pathway. EMBO J. 1997;16:706–16.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309–13.CrossRefPubMedGoogle Scholar
  8. Miyazawa M, Tsuji Y. Evidence for a novel antioxidant function and isoform-specific regulation of the human p66Shc gene. Mol Biol Cell. 2014;25:2116–27.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Nemoto S, Combs CA, French S, Ahn B-H, Fergusson MM, Balaban RS, et al. The mammalian longevity-associated gene product p66shc regulates mitochondrial metabolism. J Biol Chem. 2006;281:10555–60.CrossRefPubMedGoogle Scholar
  10. Okada S, Kao AW, Ceresa BP, Blaikie P, Margolis B, Pessin JE. The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor-stimulated mitogen-activated protein kinase pathway. J Biol Chem. 1997;272:28042–9.CrossRefPubMedGoogle Scholar
  11. Ravichandran KS. Signaling via Shc family adapter proteins. Oncogene. 2001;20:6322–30.CrossRefPubMedGoogle Scholar
  12. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, et al. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature. 1992;360:689–92.CrossRefPubMedGoogle Scholar
  13. Vikram A, Kim Y-R, Kumar S, Naqvi A, Hoffman TA, Kumar A, et al. Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species. Arterioscler Thromb Vasc Biol. 2014;34:2301–9.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiotechnologyUniversity of KashmirSrinagarIndia