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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2433-2444
M-Ras, a Widely Expressed 29-kD Homologue of p21
Ras: Expression of a Constitutively Active Mutant Results in
Factor-Independent Growth of an Interleukin-3-Dependent Cell Line
Götz R.A. Ehrhardt,
Kevin B. Leslie,
Frances Lee,
James S. Wieler, and
John W. Schrader
From The Biomedical Research Centre, University of British Columbia,
Vancouver, BC, Canada.
M-Ras, a recently identified homologue of p21 Ras, is widely
expressed, with levels of the 29-kD protein in spleen, thymus, and NIH
3T3 fibroblasts equaling or exceeding those of p21 Ras. A G22V mutant
of M-Ras was constitutively active and its expression in an
interleukin-3 (IL-3)-dependent mast cell/megakaryocyte cell line
resulted in increased survival in the absence of IL-3, increased growth
in IL-4, and, at high expression levels, in factor-independent growth.
Expression of M-Ras G22V, however, had a negative effect on growth in
the presence of IL-3, suggesting that M-Ras has both positive and
negative effects on growth. Expression of M-Ras G22V in NIH-3T3
fibroblasts resulted in morphological transformation and growth to
higher cell densities. M-Ras G22V induced activation of the
c-fos promoter, and bound weakly to the Ras-binding domains of
Raf-1 and RalGDS. Expression of a mutant of M-Ras G22V that was no
longer membrane-bound partially inhibited (40%) activation of the
c-fos promoter by N-Ras Q61K, suggesting that M-Ras shared some, but not all, of the effectors of N-Ras. An S27N mutant of M-Ras,
like the analogous H-Ras S17N mutant, was a dominant inhibitor of
activation of the c-fos promoter by constitutively active Src Y527F, suggesting that M-Ras and p21 Ras shared guanine nucleotide exchange factors and are likely to be activated in parallel. Moreover, M-Ras was recognized by the monoclonal anti-Ras antibody Y13-259, commonly used to study the function and activity of p21 Ras. Mammalian M-Ras and a Caenorhabditis elegans orthologue
exhibit conserved structural features, and these are likely to mediate
activation of distinctive signaling paths that function in parallel to
those downstream of p21 Ras.
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