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J. Biol. Chem., Vol. 266, Issue 18, 11661-11668, Jun, 1991
H Maruta, J Holden, A Sizeland and G D'Abaco
The oncogenic transformation of a normal fibroblast by mutated Ras genes
can be reversed by overexpression of a Ras-related gene called Rap1A (or
Krev1). Both Ras and Rap1A proteins are G proteins and appear to serve as
signal transducers only in the GTP-bound form. Therefore, GAP1 and GAP3,
which stimulate the intrinsic GTPase activities of normal Ras and Rap1A
proteins, respectively, serve as attenuators of their signal transducing
activities. In this paper, we describe the enzymatic properties of several
mutated Rap1A and chimeric Ras/Rap1A (or -1B) proteins which lead to the
following conclusions: (i) the GAP3- dependent activation of both Rap1A and
-1B GTPases requires Gly12, but neither Thr61 nor Gln63; (ii) residues 64
to 70 of the Rap1 GTPases are sufficient to determine their specificities
for GAP3; and (iii) residues 61 to 65 of the Ras GTPases are sufficient for
determining their specificities for GAP1. Thus, the domains of the Ras or
Rap1 proteins that determine whether their signals are attenuated by GAP1
or GAP3 are distinct from the N-terminal domain (residues 21 to 54) that
determines whether their signals are oncogenic or antioncogenic. The Arg12
mutant of chimeric HaRas(1-54)/Rap1A(55-184) protein has been previously
reported to be oncogenic (Zhang, K., Noda, M., Vass, W. C., Papageorge,
A.G., and Lowy, D.R. (1990) Science 249, 162-165). In this paper, we show
that the Val12 mutant of chimeric HaRas(1-54)/Rap1B(55- 184) protein is
also oncogenic, suggesting that the C-terminal geranylgeranylation of the
Rap 1B protein can replace functionally the C-terminal farnesylation of the
Ras protein to allow the G protein to be oncogenic.
The residues of Ras and Rap proteins that determine their GAP specificities
Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, Victoria, Australia.
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