PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis

Trever G Bivona; Steven E Quatela; Brian O Bodemann; Ian M Ahearn; Michael J Soskis; Adam Mor; John Miura; Heidi H Wiener; Latasha Wright; Shahryar G Saba; Duke Yim; Adam Fein; Ignacio Pérez de Castro; Chi Li; Craig B Thompson; Adrienne D Cox; Mark R Philips

doi:10.1016/j.molcel.2006.01.012

PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis

Mol Cell. 2006 Feb 17;21(4):481-93. doi: 10.1016/j.molcel.2006.01.012.

Authors

Trever G Bivona¹, Steven E Quatela, Brian O Bodemann, Ian M Ahearn, Michael J Soskis, Adam Mor, John Miura, Heidi H Wiener, Latasha Wright, Shahryar G Saba, Duke Yim, Adam Fein, Ignacio Pérez de Castro, Chi Li, Craig B Thompson, Adrienne D Cox, Mark R Philips

Affiliation

¹ Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

PMID: 16483930
DOI: 10.1016/j.molcel.2006.01.012

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antineoplastic Agents / metabolism
Apoptosis / physiology*
Bryostatins
Cell Line
Cell Membrane / metabolism
Genes, ras*
Humans
Intracellular Membranes / metabolism
Intracellular Signaling Peptides and Proteins / metabolism
Macrolides / metabolism
Membrane Proteins / metabolism
Mice
Mice, Nude
Mitochondria / metabolism*
Mitochondria / ultrastructure
Molecular Sequence Data
Myristoylated Alanine-Rich C Kinase Substrate
Neoplasms / metabolism
Neoplasms / pathology
Protein Isoforms / chemistry
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Kinase C / metabolism*
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Serine / metabolism
Signal Transduction / physiology
Static Electricity
T-Lymphocytes / physiology
bcl-X Protein / metabolism*

Substances

Antineoplastic Agents
Bryostatins
Intracellular Signaling Peptides and Proteins
Macrolides
Membrane Proteins
Protein Isoforms
Recombinant Fusion Proteins
bcl-X Protein
Myristoylated Alanine-Rich C Kinase Substrate
bryostatin 1
Serine
Protein Kinase C