Ras Isoforms Vary in Their Ability to Activate Raf-1 and Phosphoinositide 3-Kinase*
- From the Queensland Cancer Fund Laboratory of Experimental Oncology, Department of Pathology, University of Queensland Medical School, Herston Road, Brisbane 4006, Australia
Abstract
Ha-, N-, and Ki-Ras are ubiquitously expressed in mammalian cells and can all interact with the same set of effector proteins. We show here, however, that in vivo there are marked quantitative differences in the ability of Ki- and Ha-Ras to activate Raf-1 and phosphoinositide 3-kinase. Thus, Ki-Ras both recruits Raf-1 to the plasma membrane more efficiently than Ha-Ras and is a more potent activator of membrane-recruited Raf-1 than Ha-Ras. In contrast, Ha-Ras is a more potent activator of phosphoinositide 3-kinase than Ki-Ras. Interestingly, the ability of Ha-Ras to recruit Raf-1 to the plasma membrane is significantly increased when the Ha-Ras hypervariable region is shortened so that the spacing of the Ha-Ras GTPase domains from the inner surface of the plasma membrane mimicks that of Ki-Ras. Importantly, these data show for the first time that the activation of different Ras isoforms can have distinct biochemical consequences for the cell. The mutation of specific Ras isoforms in different human tumors can, therefore, also be rationalized.
Footnotes
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↵* This work was supported by a grant from the National Health and Medical Research Council (Australia).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by the Royal Children’s Hospital Foundation (Queensland, Australia). To whom correspondence should be addressed: Dept. of Pathology, University of Queensland Medical School, Herston Rd., Brisbane 4006, Australia. Tel.: 61-7-3365-5340; Fax: 61-7-3365-5511; E-mail: j.hancock{at}mailbox.uq.edu.au.
- Abbreviations:
- PI3-K
-
phosphoinositide 3-kinase
- HVR
-
hypervariable region
- DTT
-
dithiothreitol
- PAGE
-
polyacrylamide gel electrophoresis
- GST
-
glutathione S-transferase
- PBS
-
phosphate-buffered saline
- PIP
-
phosphatidylinositol 3′-phosphate
- MBP
-
myelin basic protein
- ERK
-
extracellular regulated kinase
- MEK
-
MAP/ERK kinase.
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- Received May 29, 1998.
- Revision received July 7, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
