Di-Ras, a Distinct Subgroup of Ras Family GTPases with Unique Biochemical Properties

Kenji Kontani, Minoru Tada, Tomohiro Ogawa, Takuro Okai, Kota Saito, Yasuhiro Araki, Toshiaki Katada
2002 Journal of Biological Chemistry  
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
more » ... 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 GTPbound 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 mitogenactivated 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. The small GTPase Ras family acts as a molecular switch that regulates a wide range of cell functions including proliferation and differentiation (1-3). Ras is activated in response to a variety of extracellular signals, resulting in stimulation of tyrosine kinases either directly or indirectly. The small GTPase, which cycles between active GTP-bound and inactive GDPbound states, is activated by guanine nucleotide exchange factors that enhance the exchange of bound GDP for GTP and is deactivated by GTPase-activating proteins that increase the intrinsic rate of hydrolysis of bound GTP. The GTP-bound form *
doi:10.1074/jbc.m202150200 pmid:12194967 fatcat:yk66lmlbuvc4diqrrogffi62by