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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TypeArticle
Journal titleMol.Cell
Volume21
Issue4
Pages481493; # of pages: 13
Subjectcell; Cells; In Vitro; Location; membrane; Membranes; Mitochondria; Pathway; Phosphorylation; plasma; protein; Region; Sequence
AbstractK-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 date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberBIVONA2006
NPARC number9389260
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Record identifier9dc39992-7048-449a-9f71-94e3d888020f
Record created2009-07-10
Record modified2016-05-09
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