ScienceDirect - Molecular Cell : PKC Regulates a = Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association = with Bcl-Xl on Mitochondria and Induces Apoptosis

From: Subject: ScienceDirect - Molecular Cell : PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association with Bcl-Xl on Mitochondria and Induces Apoptosis Date: Wed, 17 May 2006 13:36:34 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C679B6.EA039570" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C679B6.EA039570 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSR-4J8T4MB-7&_coverDate=02%2F17%2F2006&_alid=403336262&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=7053&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=41e8d1c7e2c92b5a9c431183e0981055 =EF=BB=BF ScienceDirect - Molecular Cell : PKC Regulates a = Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association = with Bcl-Xl on Mitochondria and Induces Apoptosis

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Volume=20 21, Issue 4 , 17 February 2006, Pages 481-493

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doi:10.1016/j.molcel.2006.01.012 &= nbsp; 3D"How

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Article

PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes = its=20 Association with Bcl-Xl on Mitochondria and = Induces=20 Apoptosis

Trever G. Bivona²^,=20⁷,=20 Steven E. Quatela³^,=20⁷,=20 Brian O. Bodemann⁵,=20 Ian M. Ahearn²,=20 Michael J. Soskis²,=20 Adam Mor¹,=20 John Miura³,=20 Heidi H. Wiener²,=20 Latasha Wright²,=20 Shahryar G. Saba²,=20 Duke Yim²,=20 Adam Fein²,=20 Ignacio P=C3=A9rez de Castro⁴^,=20⁸,=20 Chi Li⁶,=20 Craig B. Thompson⁶,=20 Adrienne D. Cox⁵=20 and Mark R. Philips¹^,=20²^,=20³^,=20^,

¹Department of=20 Medicine, New York University School of Medicine, 550 First Avenue, New = York,=20 New York 10016
²Department of Cell = Biology, New=20 York University School of Medicine, 550 First Avenue, New York, New York = 10016
³Department of Pharmacology, New = York=20 University School of Medicine, 550 First Avenue, New York, New York = 10016
⁴Department of Pathology, New York University = School of=20 Medicine, 550 First Avenue, New York, New York 10016
⁵Departments of Radiation Oncology and = Pharmacology,=20 University of North Carolina at Chapel Hill School of Medicine, 101 = Manning=20 Drive, Chapel Hill, North Carolina 27599
⁶Department of Cancer Biology, University of=20 Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, = Pennsylvania=20 19104

Received 15 May 2005; revised 12 December = 2005; =20 accepted 5 January 2006. Published: February 16, 2006. = Available=20 online 16 February 2006.

Summary

K-Ras associates with the plasma membrane (PM) through farnesylation = that=20 functions in conjunction with an adjacent polybasic sequence. We show = that=20 phosphorylation by protein kinase C (PKC) of S181 within the polybasic = region=20 promotes rapid dissociation of K-Ras from the PM and association with=20 intracellular membranes, including the outer membrane of mitochondria = where=20 phospho-K-Ras interacts with Bcl-Xl. PKC = agonists=20 promote apoptosis of cells transformed with oncogenic K-Ras in a = S181-dependent=20 manner. K-Ras with a phosphomimetic residue at position 181 induces = apoptosis=20 via a pathway that requires Bcl-Xl. The PKC = agonist=20 bryostatin-1 inhibited the growth in vitro and in vivo of cells = transformed with=20 oncogenic K-Ras in a S181-dependent fashion. These data demonstrate that = the=20 location and function of K-Ras are regulated directly by PKC and suggest = an=20 approach to therapy of K-Ras-dependent tumors with agents that stimulate = phosphorylation of S181.=20

Author Keywords: SIGNALING; PROTEINS; CELLCYCLE 3D""=20

Ph: (212) 263-7404; Fax: (212) 263-0759
⁷ These authors contributed equally to = this=20 work.
⁸ Present address: Molecular = Oncology=20 Program, Spanish National Cancer Center, Melchor Fernandez Almagro, 3, = 28029=20 Madrid, Spain.

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Molecu= lar=20 Cell
Volume=20 21, Issue 4 , 17 February 2006, Pages 481-493=20

Copyright =C2=A9 = 2006 Elsevier = B.V. All rights=20 reserved. ScienceDirect=C2=AE is a registered trademark of = Elsevier=20 B.V.

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