PKC Regulates a Farnesyl-Electrostatic Switch on K-Ras that Promotes its Association with Bcl-Xl on Mitochondria and Induces Apoptosis
| Autor: | Adam Mor, Ignacio Pérez de Castro, Chi Li, Brian O. Bodemann, Michael J. Soskis, Adrienne D. Cox, Shahryar G Saba, Duke Yim, John Miura, Ian M. Ahearn, Adam Fein, Trever G. Bivona, Mark R. Philips, Steven E. Quatela, Latasha Wright, Heidi H. Wiener, Craig B. Thompson |
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| Rok vydání: | 2006 |
| Předmět: |
T-Lymphocytes
Apoptosis Mitochondrion Mice Neoplasms Serine Protein Isoforms Region Phosphorylation Myristoylated Alanine-Rich C Kinase Substrate membrane Protein Kinase C biology Intracellular Signaling Peptides and Proteins Cell cycle Bryostatins Mitochondria Cell biology In Vitro Macrolides Intracellular Signal Transduction Recombinant Fusion Proteins Cells Location Molecular Sequence Data Static Electricity bcl-X Protein Mice Nude Antineoplastic Agents Bcl-xL Cell Line Prenylation Sequence Animals Humans Amino Acid Sequence Molecular Biology plasma Protein kinase C Membranes Cell Membrane Membrane Proteins Intracellular Membranes Cell Biology cell Genes ras biology.protein protein Pathway |
| Zdroj: | Molecular Cell. 21:481-493 |
| ISSN: | 1097-2765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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