Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway
The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that interact with histidine kinases throughout evolution may represent partners for Nm23...
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| Veröffentlicht in: | The Journal of biological chemistry 2002-08, Vol.277 (35), p.32389-32399 |
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| container_title | The Journal of biological chemistry |
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| creator | Hartsough, Melanie T Morrison, Deborah K Salerno, Massimiliano Palmieri, Diane Ouatas, Taoufik Mair, Michael Patrick, Jilma Steeg, Patricia S |
| description | The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that
interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of
Arabidopsis âtwo-componentâ histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report
that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein
kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous
protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR
in vitro . Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified
upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that
Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated
MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis. |
| doi_str_mv | 10.1074/jbc.M203115200 |
| format | Article |
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interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of
Arabidopsis âtwo-componentâ histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report
that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein
kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous
protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR
in vitro . Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified
upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that
Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated
MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M203115200</identifier><identifier>PMID: 12105213</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Alanine ; Amino Acid Substitution ; Antigens, Neoplasm - metabolism ; Base Sequence ; Breast Neoplasms ; Cell Line ; DNA Primers ; Female ; Histidine Kinase ; Humans ; Kinetics ; Monomeric GTP-Binding Proteins - chemistry ; Monomeric GTP-Binding Proteins - genetics ; Monomeric GTP-Binding Proteins - metabolism ; Mutagenesis, Site-Directed ; Neoplasm Metastasis - prevention & control ; NM23 Nucleoside Diphosphate Kinases ; Nucleoside-Diphosphate Kinase ; Phosphorylation ; Protein Kinases - metabolism ; ras Proteins - antagonists & inhibitors ; ras Proteins - metabolism ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Serine ; Substrate Specificity ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transfection ; Tumor Cells, Cultured</subject><ispartof>The Journal of biological chemistry, 2002-08, Vol.277 (35), p.32389-32399</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-f21ccbbad157748a49b89a582469e0e49e5dfbec406efb0385d88e3dba9a50df3</citedby><cites>FETCH-LOGICAL-c457t-f21ccbbad157748a49b89a582469e0e49e5dfbec406efb0385d88e3dba9a50df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12105213$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hartsough, Melanie T</creatorcontrib><creatorcontrib>Morrison, Deborah K</creatorcontrib><creatorcontrib>Salerno, Massimiliano</creatorcontrib><creatorcontrib>Palmieri, Diane</creatorcontrib><creatorcontrib>Ouatas, Taoufik</creatorcontrib><creatorcontrib>Mair, Michael</creatorcontrib><creatorcontrib>Patrick, Jilma</creatorcontrib><creatorcontrib>Steeg, Patricia S</creatorcontrib><title>Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that
interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of
Arabidopsis âtwo-componentâ histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report
that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein
kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous
protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR
in vitro . Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified
upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that
Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated
MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.</description><subject>Alanine</subject><subject>Amino Acid Substitution</subject><subject>Antigens, Neoplasm - metabolism</subject><subject>Base Sequence</subject><subject>Breast Neoplasms</subject><subject>Cell Line</subject><subject>DNA Primers</subject><subject>Female</subject><subject>Histidine Kinase</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Monomeric GTP-Binding Proteins - chemistry</subject><subject>Monomeric GTP-Binding Proteins - genetics</subject><subject>Monomeric GTP-Binding Proteins - metabolism</subject><subject>Mutagenesis, Site-Directed</subject><subject>Neoplasm Metastasis - prevention & control</subject><subject>NM23 Nucleoside Diphosphate Kinases</subject><subject>Nucleoside-Diphosphate Kinase</subject><subject>Phosphorylation</subject><subject>Protein Kinases - metabolism</subject><subject>ras Proteins - antagonists & inhibitors</subject><subject>ras Proteins - metabolism</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Serine</subject><subject>Substrate Specificity</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkE1LxDAQhoMoun5cPUoO4q3rJGlsehRRV_xa_ABvIWmnNrJtatJ12X9vZVd0GBgYnvc9PIQcMhgzyNLTD1uM7zkIxiQH2CAjBkokQrK3TTIC4CzJuVQ7ZDfGDxgmzdk22WGcgeRMjEj30HCRTBi9x97EYV2kz_OuCxijD3Ra-9jVPixnpne-pb6it641Ef9Dw_PJRPrlDDV04mLvStcinQbfo2t_A1PT1wuz3CdblZlFPFjfPfJ6dflyMUnuHq9vLs7vkiKVWZ9UnBWFtaZkMstSZdLcqtxIxdOzHAHTHGVZWSxSOMPKglCyVApFac1AQVmJPXKy6u2C_5xj7HXjYoGzmWnRz6NmSioAkQ_geAUWwccYsNJdcI0JS81A_zjWg2P953gIHK2b57bB8g9fSx2A4xVQu_d64QJq63xRY6N5lmkhteBC5eIbxm6E3g</recordid><startdate>20020830</startdate><enddate>20020830</enddate><creator>Hartsough, Melanie T</creator><creator>Morrison, Deborah K</creator><creator>Salerno, Massimiliano</creator><creator>Palmieri, Diane</creator><creator>Ouatas, Taoufik</creator><creator>Mair, Michael</creator><creator>Patrick, Jilma</creator><creator>Steeg, Patricia S</creator><general>American Society for Biochemistry and Molecular Biology</general><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>7TO</scope><scope>H94</scope></search><sort><creationdate>20020830</creationdate><title>Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway</title><author>Hartsough, Melanie T ; Morrison, Deborah K ; Salerno, Massimiliano ; Palmieri, Diane ; Ouatas, Taoufik ; Mair, Michael ; Patrick, Jilma ; Steeg, Patricia S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-f21ccbbad157748a49b89a582469e0e49e5dfbec406efb0385d88e3dba9a50df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Alanine</topic><topic>Amino Acid Substitution</topic><topic>Antigens, Neoplasm - metabolism</topic><topic>Base Sequence</topic><topic>Breast Neoplasms</topic><topic>Cell Line</topic><topic>DNA Primers</topic><topic>Female</topic><topic>Histidine Kinase</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Monomeric GTP-Binding Proteins - chemistry</topic><topic>Monomeric GTP-Binding Proteins - genetics</topic><topic>Monomeric GTP-Binding Proteins - metabolism</topic><topic>Mutagenesis, Site-Directed</topic><topic>Neoplasm Metastasis - prevention & control</topic><topic>NM23 Nucleoside Diphosphate Kinases</topic><topic>Nucleoside-Diphosphate Kinase</topic><topic>Phosphorylation</topic><topic>Protein Kinases - metabolism</topic><topic>ras Proteins - antagonists & inhibitors</topic><topic>ras Proteins - metabolism</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>Serine</topic><topic>Substrate Specificity</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hartsough, Melanie T</creatorcontrib><creatorcontrib>Morrison, Deborah K</creatorcontrib><creatorcontrib>Salerno, Massimiliano</creatorcontrib><creatorcontrib>Palmieri, Diane</creatorcontrib><creatorcontrib>Ouatas, Taoufik</creatorcontrib><creatorcontrib>Mair, Michael</creatorcontrib><creatorcontrib>Patrick, Jilma</creatorcontrib><creatorcontrib>Steeg, Patricia S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hartsough, Melanie T</au><au>Morrison, Deborah K</au><au>Salerno, Massimiliano</au><au>Palmieri, Diane</au><au>Ouatas, Taoufik</au><au>Mair, Michael</au><au>Patrick, Jilma</au><au>Steeg, Patricia S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-08-30</date><risdate>2002</risdate><volume>277</volume><issue>35</issue><spage>32389</spage><epage>32399</epage><pages>32389-32399</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that
interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of
Arabidopsis âtwo-componentâ histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report
that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein
kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous
protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR
in vitro . Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified
upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that
Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated
MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12105213</pmid><doi>10.1074/jbc.M203115200</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2002-08, Vol.277 (35), p.32389-32399 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Alanine Amino Acid Substitution Antigens, Neoplasm - metabolism Base Sequence Breast Neoplasms Cell Line DNA Primers Female Histidine Kinase Humans Kinetics Monomeric GTP-Binding Proteins - chemistry Monomeric GTP-Binding Proteins - genetics Monomeric GTP-Binding Proteins - metabolism Mutagenesis, Site-Directed Neoplasm Metastasis - prevention & control NM23 Nucleoside Diphosphate Kinases Nucleoside-Diphosphate Kinase Phosphorylation Protein Kinases - metabolism ras Proteins - antagonists & inhibitors ras Proteins - metabolism Recombinant Proteins - chemistry Recombinant Proteins - metabolism Serine Substrate Specificity Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Transfection Tumor Cells, Cultured |
| title | Nm23-H1 Metastasis Suppressor Phosphorylation of Kinase Suppressor of Ras via a Histidine Protein Kinase Pathway |
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