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 int...
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| Veröffentlicht in: | Molecular cell 2006-02, Vol.21 (4), p.481-493 |
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| creator | Bivona, Trever G Quatela, Steven E Bodemann, Brian O Ahearn, Ian M Soskis, Michael J Mor, Adam Miura, John Wiener, Heidi H Wright, Latasha Saba, Shahryar G Yim, Duke Fein, Adam Pérez de Castro, Ignacio Li, Chi Thompson, Craig B Cox, Adrienne D Philips, Mark R |
| description | 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. |
| doi_str_mv | 10.1016/j.molcel.2006.01.012 |
| format | Article |
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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. 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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.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Apoptosis - physiology</subject><subject>bcl-X Protein - metabolism</subject><subject>Bryostatins</subject><subject>Cell Line</subject><subject>Cell Membrane - metabolism</subject><subject>Genes, ras</subject><subject>Humans</subject><subject>Intracellular Membranes - metabolism</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Macrolides - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - ultrastructure</subject><subject>Molecular Sequence Data</subject><subject>Myristoylated Alanine-Rich C Kinase Substrate</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Kinase C - metabolism</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Serine - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Static Electricity</subject><subject>T-Lymphocytes - physiology</subject><issn>1097-2765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1KxDAUhbNQnHH0DUSy0lVr0jRputTBPxxQRMFduJOmToa2GZsUmRfwuU2ZAXfChbv5zv05B6EzSlJKqLhap61rtGnSjBCREhorO0BTSsoiyQrBJ-jY-zUhNOeyPEITKnLJSkam6OflaY578zk0EIzHgGvoO-O3TWIao0PvfIBgNfbfNugVdh1-Sl7B47CCgDe9a90osyFKvXfaRjgyEV7hG90kH4tR0trg9Mp1VW8BQ1dh21WDHtdt3CY4b_0JOqyh8eZ032fo_e72bf6QLJ7vH-fXi0QzyUKyLEGDqXKScyFYIatM0vjHktWkrIHxwpQZZJnIl2AE5bzistYyJ5BrVuhCsxm63M2Np38NxgfVWh-Na6AzbvAqusIlF1JG8uJfUhRClPGGCOY7UEezfG9qteltC_1WUaLGdNRa7dJRYzqK0FhZlJ3v5w_L1lR_on007Bc1JpFL</recordid><startdate>20060217</startdate><enddate>20060217</enddate><creator>Bivona, Trever G</creator><creator>Quatela, Steven E</creator><creator>Bodemann, Brian O</creator><creator>Ahearn, Ian M</creator><creator>Soskis, Michael J</creator><creator>Mor, Adam</creator><creator>Miura, John</creator><creator>Wiener, Heidi H</creator><creator>Wright, Latasha</creator><creator>Saba, Shahryar G</creator><creator>Yim, Duke</creator><creator>Fein, Adam</creator><creator>Pérez de Castro, Ignacio</creator><creator>Li, Chi</creator><creator>Thompson, Craig B</creator><creator>Cox, Adrienne D</creator><creator>Philips, Mark R</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TO</scope><scope>H94</scope></search><sort><creationdate>20060217</creationdate><title>PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis</title><author>Bivona, Trever G ; Quatela, Steven E ; Bodemann, Brian O ; Ahearn, Ian M ; Soskis, Michael J ; Mor, Adam ; Miura, John ; Wiener, Heidi H ; Wright, Latasha ; Saba, Shahryar G ; Yim, Duke ; Fein, Adam ; Pérez de Castro, Ignacio ; Li, Chi ; Thompson, Craig B ; Cox, Adrienne D ; Philips, Mark R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-b9acaed404566378d281393b3f09fa357e92a2264bae6155d58fc840a4c37c7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Apoptosis - physiology</topic><topic>bcl-X Protein - metabolism</topic><topic>Bryostatins</topic><topic>Cell Line</topic><topic>Cell Membrane - metabolism</topic><topic>Genes, ras</topic><topic>Humans</topic><topic>Intracellular Membranes - metabolism</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Macrolides - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - ultrastructure</topic><topic>Molecular Sequence Data</topic><topic>Myristoylated Alanine-Rich C Kinase Substrate</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Protein Isoforms - chemistry</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Kinase C - metabolism</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Serine - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Static Electricity</topic><topic>T-Lymphocytes - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bivona, Trever G</creatorcontrib><creatorcontrib>Quatela, Steven E</creatorcontrib><creatorcontrib>Bodemann, Brian O</creatorcontrib><creatorcontrib>Ahearn, Ian M</creatorcontrib><creatorcontrib>Soskis, Michael J</creatorcontrib><creatorcontrib>Mor, Adam</creatorcontrib><creatorcontrib>Miura, John</creatorcontrib><creatorcontrib>Wiener, Heidi H</creatorcontrib><creatorcontrib>Wright, Latasha</creatorcontrib><creatorcontrib>Saba, Shahryar G</creatorcontrib><creatorcontrib>Yim, Duke</creatorcontrib><creatorcontrib>Fein, Adam</creatorcontrib><creatorcontrib>Pérez de Castro, Ignacio</creatorcontrib><creatorcontrib>Li, Chi</creatorcontrib><creatorcontrib>Thompson, Craig B</creatorcontrib><creatorcontrib>Cox, Adrienne D</creatorcontrib><creatorcontrib>Philips, Mark R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bivona, Trever G</au><au>Quatela, Steven E</au><au>Bodemann, Brian O</au><au>Ahearn, Ian M</au><au>Soskis, Michael J</au><au>Mor, Adam</au><au>Miura, John</au><au>Wiener, Heidi H</au><au>Wright, Latasha</au><au>Saba, Shahryar G</au><au>Yim, Duke</au><au>Fein, Adam</au><au>Pérez de Castro, Ignacio</au><au>Li, Chi</au><au>Thompson, Craig B</au><au>Cox, Adrienne D</au><au>Philips, Mark R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2006-02-17</date><risdate>2006</risdate><volume>21</volume><issue>4</issue><spage>481</spage><epage>493</epage><pages>481-493</pages><issn>1097-2765</issn><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.</abstract><cop>United States</cop><pmid>16483930</pmid><doi>10.1016/j.molcel.2006.01.012</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Animals Antineoplastic Agents - metabolism Apoptosis - physiology bcl-X Protein - metabolism 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 |
| title | 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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