F. Al-mulla et al., Structural differences between valine-12 and aspartate-12 Ras proteins maymodify carcinoma aggression, J PATHOLOGY, 187(4), 1999, pp. 433-438
Citations number
34
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Recent evidence associates the codon 12 valine-for-glycine (G12V) mutant Ki
-Ras protein with higher stage and increased lethality of colorectal carcin
omas, while the codon 12 aspartate-far-glycine (G12D) Ras mutation shows no
such association. Several observations may be relevant to this phenomenon,
First, GTPase activity of G12Y Ras is one-quarter that of G12D Ras and one
-tenth that of wild-type (WT) Pas. Second, binding of the GTP analogue GppN
p to G12D Ras is 8-fold weaker than its binding to G12V or WT Ras and cryst
al structures indicate that electrostatic repulsion between the carboxylate
group of the G12D Asp-12 side-chain and the gamma phosphate of the bound n
ucleotide may make GTP binding to G12D Pas weaker even than that of GppNp,
It is proposed that this lowering of affinity for GTP allows G12D Pas an es
cape From the oncogenic GTP-bound state, whereas GTP tightly bound to G12V
mutant Ras generates a more persistent, potentially oncogenic, signal. Stru
ctural comparisons also suggest that differences between the Switch I (effe
ctor) region of G12D and G12V Pas could modify interactions with downstream
signalling molecules such as Raf-l, neurofibromin, and phosphatidylinosito
l 3-hydroxy-kinase. Other differences between the G12D and G12V mutant Ras
proteins include a lower affinity of the GTPase activating protein GAP for
G12V than for G12D or WT Ras; but, as both G12D and G12V Pas are refractory
to GTPase activation by GAP binding, this may be less significant, These s
tudies complement experimental data showing that such Ras mutations differ
in their effects in vitro and in vivo and, with recent data indicating hete
rogeneity of uas mutation in colorectal carcinomas and other tumours, make
it plausible that codon 12 Pas mutations differ in carcinogenic potential a
nd prognostic significance. Copyright (C) 1999 John Wiley & Sons, Ltd.