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

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Bivona TG,Quatela SE,Bodemann BO,Ahearn IM,Soskis MJ,Mor A,Miura J,Wiener HH,Wright L,Saba SG,Yim D,Fein A,Pérez de Castro I,Li C,Thompson CB,Cox AD,Philips MR

doi

10.1016/j.molcel.2006.01.012

subject

Has Abstract

pub_date

2006-02-17 00:00:00

pages

481-93

issue

4

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(06)00032-3

journal_volume

21

pub_type

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