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J. Biol. Chem., Vol. 277, Issue 1, 272-278, January 4, 2002
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From the Laboratory of Experimental Oncology, Department of
Pathology, University of Queensland Medical School, Herston Road,
Queensland 4006, Australia
Ha-Ras and Ki-Ras have different distributions
across plasma membrane microdomains. The Ras C-terminal anchors are
primarily responsible for membrane micro-localization, but recent work
has shown that the interaction of Ha-Ras with lipid rafts is modulated by GTP loading via a mechanism that requires the hypervariable region
(HVR). We have now identified two regions in the HVR linker domain that
regulate Ha-Ras raft association. Release of activated Ha-Ras from
lipid rafts is blocked by deleting amino acids 173-179 or 166-172.
Alanine replacement of amino acids 173-179 but not 166-172 restores
wild type micro-localization, indicating that specific N-terminal
sequences of the linker domain operate in concert with a more
C-terminal spacer domain to regulate Ha-Ras raft association. Mutations
in the linker domain that confine activated Ha-RasG12V to lipid rafts
abrogate Raf-1, phosphoinositide 3-kinase, and Akt activation and
inhibit PC12 cell differentiation. N-Myristoylation also
prevents the release of activated Ha-Ras from lipid rafts and inhibits
Raf-1 activation. These results demonstrate that the correct modulation
of Ha-Ras lateral segregation is critical for downstream signaling.
Mutations in the linker domain also suppress the dominant negative
phenotype of Ha-RasS17N, indicating that HVR sequences are essential
for efficient interaction of Ha-Ras with exchange factors in
intact cells.
The Linker Domain of the Ha-Ras Hypervariable Region
Regulates Interactions with Exchange Factors, Raf-1 and
Phosphoinositide 3-Kinase*
,,
*
This work was supported by grants from the National Health
and Medical Research Council of 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.
These authors contributed equally to this work.
§
Supported by the Royal Children's Hospital Foundation, Queensland.
To whom correspondence should be addressed: Tel.: 61-7-3365-5288; Fax:
61-7-3365-5511; E-mail: j.hancock@mailbox.uq.edu.au.
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