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

被引:34
作者
Edouard, T.
Montagner, A.
Dance, M.
Conte, F.
Yart, A.
Parfait, B.
Tauber, M.
Salles, J. P.
Raynal, P.
机构
[1] INSERM, Dept Lipoprot & Mediateurs Lipid, U563, F-31024 Toulouse, France
[2] Univ Paris 05, INSERM, U745, F-75270 Paris, France
关键词
SHP-2; PTPN11; Noonan syndrome; LEOPARD syndrome; Gab1; Ras;
D O I
10.1007/s00018-007-6509-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1585 / 1590
页数:6
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