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.

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