Di-Ras, a distinct subgroup of ras family GTPases with unique biochemical properties.
The small GTPase Ras family regulates a variety of cell functions including proliferation and differentiation. Here we have identified novel Ras members, human Di-Ras1 and Di-Ras2, belonging to a distinct branch of the GTPase family. Di-Ras1 and Di-Ras2 specifically expressed in heart and brain share 30-40% overall identity with other members of Ras family, however, they have the following characteristic substitutions at highly conserved regions among the Ras family. 1) Thr-63 and Ser-65 in Di-Ras are substituted for Ala-59 and Gln-61 positions in Ha-Ras, respectively, that are known to be critical for GTP hydrolysis. 2) Within the effector domains, Di-Ras has Ile at a position corresponding to Asp-33 in Ha-Ras, which is important for its interaction with the downstream effector Raf. As predicted by these substitutions, Di-Ras has only a quite low level of GTPase activity and exists predominantly as a GTP-bound form upon its expression in living cells. Moreover, Di-Ras fails to interact with the Ras-binding domain of Raf, resulting in no stimulation of mitogen-activated protein kinase. Interestingly, introduction of Di-Ras into HEK293T cells induces large cellular vacuolation. These findings raise the possibility that Di-Ras might regulate cell morphogenesis in a manner distinct from other members of Ras family.
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Tokyo 113-0033, Japan.
Kenji
K
Kontani
Minoru
M
Tada
Tomohiro
T
Ogawa
Takuro
T
Okai
Kota
K
Saito
Yasuhiro
Y
Araki
Toshiaki
T
Katada
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D025521:Tumor Suppressor Proteins; C468772:DIRAS1 protein, human; D020558:GTP Phosphohydrolases; D018631:ras Proteins