PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis.
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.
Bivona
Trever G
TG
Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Quatela
Steven E
SE
Bodemann
Brian O
BO
Ahearn
Ian M
IM
Soskis
Michael J
MJ
Mor
Adam
A
Miura
John
J
Wiener
Heidi H
HH
Wright
Latasha
L
Saba
Shahryar G
SG
Yim
Duke
D
Fein
Adam
A
Pérez de Castro
Ignacio
I
Li
Chi
C
Thompson
Craig B
CB
Cox
Adrienne D
AD
Philips
Mark R
MR
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D054713:Bryostatins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018942:Macrolides / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055672:Static Electricity; D013601:T-Lymphocytes / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; D054713:Bryostatins; D047908:Intracellular Signaling Peptides and Proteins; D018942:Macrolides; D008565:Membrane Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C046785:bryostatin 1; D012694:Serine; D011493:Protein Kinase C