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Etiology and Pathogenesis
> Cell Biology
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Molecular Cell, Volume 21, Issue 4, 17 February 2006, Pages 481-493. (Laboratory
Investigation)
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Abstract |
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PKC
Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its
Association with Bcl-XL on Mitochondria and Induces
Apoptosis
Trever
G. Bivona,2,7
Steven E. Quatela,3,7
Brian O. Bodemann,5
Ian M. Ahearn,2
Michael J. Soskis,2
Adam Mor,1
John Miura,3
Heidi H. Wiener,2
Latasha Wright,2
Shahryar G. Saba,2
Duke Yim,2
Adam Fein,2
Ignacio Pérez de Castro,4,8
Chi Li,6
Craig B. Thompson,6
Adrienne D. Cox,5
and Mark
R. Philips1,2,3,*
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1Department
of Medicine, New York University School of Medicine, 550 First Avenue,
New York, New York 10016.
2Department
of Cell Biology, New York University School of Medicine, 550 First
Avenue, New York, New York 10016.
3Department
of Pharmacology, New York University School of Medicine, 550 First
Avenue, New York, New York 10016.
4Department
of Pathology, New York University School of Medicine, 550 First
Avenue, New York, New York 10016.
5Departments
of Radiation Oncology and Pharmacology, University of North Carolina
at Chapel Hill School of Medicine, 101 Manning Drive, Chapel Hill,
North Carolina 27599.
6Department
of Cancer Biology, University of Pennsylvania School of Medicine, 421
Curie Boulevard, Philadelphia, Pennsylvania 19104. 7These
authors contributed equally to this work. 8Present address:
Molecular Oncology Program, Spanish National Cancer Center, Melchor
Fernandez Almagro, 3, 28029 Madrid, Spain. *Correspondence:
Mark R. Philips, Ph: (212) 263-7404; Fax: (212) 263-0759,
E-mail: philim01@med.nyu.edu.
Received 15 May 2005; revised 12 December 2005; accepted 5
January 2006. Published: February 16, 2006. Available online 16
February 2006.
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K-Ras associates
with the plasma membrane (PM) through farnesylation that functions in
conjunction with an adjacent polybasic sequence.
We show that phosphorylation by protein
kinase C (PKC) of S181 within the polybasic region promotes rapid
dissociation of K-Ras from the PM and association with intracellular
membranes, including the outer membrane of mitochondria where
phospho-K-Ras interacts with Bcl-XL.
PKC agonists promote apoptosis of cells
transformed with oncogenic K-Ras in a S181-dependent manner.
K-Ras with a phosphomimetic residue at
position 181 induces apoptosis via a pathway that requires Bcl-XL.
The PKC agonist bryostatin-1 inhibited the
growth in vitro and in vivo of cells transformed with oncogenic K-Ras
in a S181-dependent fashion.
These data demonstrate that the location
and function of K-Ras are regulated directly by PKC and suggest an
approach to therapy of K-Ras-dependent tumors with agents that
stimulate phosphorylation of S181.
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Author Keywords: Signaling, Proteins, Cellcycle
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Copyright © 2006 Elsevier B.V.
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DOI: http://dx.doi.org/10.1016/j.molcel.2006.01.012
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Source: http://www.molecule.org/content/article/abstract?uid=PIIS1097276506000323
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