Cellular and Molecular Life Sciences

, Volume 64, Issue 13, pp 1585–1590

How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?

  • T. Edouard
  • A. Montagner
  • M. Dance
  • F. Conte
  • A. Yart
  • B. Parfait
  • M. Tauber
  • J. P. Salles
  • P. Raynal
Visions & Reflections (Minireview)

DOI: 10.1007/s00018-007-6509-0

Cite this article as:
Edouard, T., Montagner, A., Dance, M. et al. Cell. Mol. Life Sci. (2007) 64: 1585. doi:10.1007/s00018-007-6509-0

Abstract.

Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes. Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1, Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the possibility that LS mutations may not simply exhibit dominant negative activity.

Keywords.

SHP-2PTPN11Noonan syndromeLEOPARD syndromeGab1Ras

Copyright information

© Birkhäuser Verlag, Basel 2007

Authors and Affiliations

  • T. Edouard
    • 1
  • A. Montagner
    • 1
  • M. Dance
    • 1
  • F. Conte
    • 1
  • A. Yart
    • 1
  • B. Parfait
    • 2
  • M. Tauber
    • 1
  • J. P. Salles
    • 1
  • P. Raynal
    • 1
  1. 1.Dept. Lipoprotéines et Médiateurs LipidiquesINSERM U563ToulouseFrance
  2. 2.INSERM U745, Université Paris 5ParisFrance