TY - JOUR
T1 - Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells
AU - Im, Edward
AU - Von Lintig, Friederike C.
AU - Chen, Jeffrey
AU - Zhuang, Shunhui
AU - Qui, Wansong
AU - Chowdhury, Shoaib
AU - Worley, Paul F.
AU - Boss, Gerry R.
AU - Pilz, Renate B.
N1 - Funding Information:
This work was supported in part by USPHS Grants GM55586 (to RB Pilz), CA76968 and CA81115 (to GR Boss) and MH53608 (to PF Worley); E Im was supported by a UCSD Institute for Research on Aging Scholarship. We thank G Johnson, M Karin, L Quilliam, P Stork and M Wigler for generously providing the indicated plasmids.
PY - 2002
Y1 - 2002
N2 - Rheb (Ras homolog enriched in brain) is a member of the Ras family of proteins, and is in the immediate Ras/Rap/Ral subfamily. We found in three different mammalian cell lines that Rbeb was highly activated, to levels much higher than for Ras or Rap 1, and that Rheb's activation state was unaffected by changes in growth conditions. Rheb's high activation was not secondary to unique glycine to arginine, or glycine to serine substitutions at positions 14 and 15, corresponding to Ras residues 12 and 13, since Rheb R14G and R14G, S15G mutants had similarly high activation levels as wild type Rheb. These data are consistent with earlier work which showed that purified Rheb has similar GTPase activity as Ras, and suggest a relative intracellular deficiency of Rheb GTPase activating proteins (GAPs) compared to Rheb activators. Further evidence for relatively low intracellular GAP activity was that increased Rheb expression led to a marked increase in Rheb activation. Rheb, like Ras and Rap1, bound B-Raf kinase, but in contrast to Ras and Rap 1, Rheb inhibited B-Raf kinase activity and prevented B-Raf-dependent activation of the transcription factor Elk-1. Thus, Rheb appears to be a unique member of the Ras/Rap/Ral subfamily, and in mammalian systems may serve to regulate B-Raf kinase activity.
AB - Rheb (Ras homolog enriched in brain) is a member of the Ras family of proteins, and is in the immediate Ras/Rap/Ral subfamily. We found in three different mammalian cell lines that Rbeb was highly activated, to levels much higher than for Ras or Rap 1, and that Rheb's activation state was unaffected by changes in growth conditions. Rheb's high activation was not secondary to unique glycine to arginine, or glycine to serine substitutions at positions 14 and 15, corresponding to Ras residues 12 and 13, since Rheb R14G and R14G, S15G mutants had similarly high activation levels as wild type Rheb. These data are consistent with earlier work which showed that purified Rheb has similar GTPase activity as Ras, and suggest a relative intracellular deficiency of Rheb GTPase activating proteins (GAPs) compared to Rheb activators. Further evidence for relatively low intracellular GAP activity was that increased Rheb expression led to a marked increase in Rheb activation. Rheb, like Ras and Rap1, bound B-Raf kinase, but in contrast to Ras and Rap 1, Rheb inhibited B-Raf kinase activity and prevented B-Raf-dependent activation of the transcription factor Elk-1. Thus, Rheb appears to be a unique member of the Ras/Rap/Ral subfamily, and in mammalian systems may serve to regulate B-Raf kinase activity.
KW - B-Raf kinase
KW - MAP kinase
KW - Mammalian cells
KW - Rheb
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U2 - 10.1038/sj.onc.1205792
DO - 10.1038/sj.onc.1205792
M3 - Article
C2 - 12214276
AN - SCOPUS:0037068783
SN - 0950-9232
VL - 21
SP - 6356
EP - 6365
JO - Oncogene
JF - Oncogene
IS - 41
ER -