A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases
Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an au...
Gespeichert in:
| Veröffentlicht in: | Molecular Cell 2007-09, Vol.27 (5), p.717-730 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 730 |
|---|---|
| container_issue | 5 |
| container_start_page | 717 |
| container_title | Molecular Cell |
| container_volume | 27 |
| creator | Chen, Huaibin Ma, Jinghong Li, Wanqing Eliseenkova, Anna V. Xu, Chongfeng Neubert, Thomas A. Miller, W. Todd Mohammadi, Moosa |
| description | Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory “molecular brake” mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly. |
| doi_str_mv | 10.1016/j.molcel.2007.06.028 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2094128</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1097276507004406</els_id><sourcerecordid>68239192</sourcerecordid><originalsourceid>FETCH-LOGICAL-c553t-278759b6e64aab4d0ee6d66a0c9d93654814cae7af2a0cfc81b2ec7bc059ee5e3</originalsourceid><addsrcrecordid>eNp9UU1vGyEQRVGj5qP9B1FFL7l5CyzLLpdKTpQvNVWlKj1Tlp21cdfgALbkfx82dpPm0tMg5s2bN-8hdEZJQQkVXxbF0g8GhoIRUhdEFIQ1B-iYEllPOBX83f7NalEdoZMYF4RQXjXyPTqidUNKWdbH6PcUf_cDmPWgA74I-g9g63CaA_5mnY6Ab62bAf4JM-vdWDIwQXxGTE2yG5u22Pe5Y2CVfMAP2-CjdX_n4wd02Oshwsd9PUW_rq8eLm8n9z9u7i6n9xNTVWXKKpu6kq0AwbVueUcARCeEJkZ2shQVbyg3Gmrds_zXm4a2DEzdGlJJgArKU_R1x7tat0voDLgU9KBWwS512CqvrXrbcXauZn6jGJGcsiYTfN4R-JisisYmMHPjnQOTlCxH8zLmfL8k-Mc1xKSWNuYMBu3Ar6MSDSsllSwD-Q5oshsxQP8ihBI1xqcWahefGuNTRCjyrOHTv0e8Du3zer0SspUbC2EUCs5AZ8Oos_P2_xueADmRr38</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>68239192</pqid></control><display><type>article</type><title>A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Elsevier ScienceDirect Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Chen, Huaibin ; Ma, Jinghong ; Li, Wanqing ; Eliseenkova, Anna V. ; Xu, Chongfeng ; Neubert, Thomas A. ; Miller, W. Todd ; Mohammadi, Moosa</creator><creatorcontrib>Chen, Huaibin ; Ma, Jinghong ; Li, Wanqing ; Eliseenkova, Anna V. ; Xu, Chongfeng ; Neubert, Thomas A. ; Miller, W. Todd ; Mohammadi, Moosa ; Brookhaven National Laboratory (BNL) National Synchrotron Light Source</creatorcontrib><description>Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory “molecular brake” mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2007.06.028</identifier><identifier>PMID: 17803937</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; CRYSTAL STRUCTURE ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Hydrogen Bonding ; MATERIALS SCIENCE ; Models, Molecular ; Molecular Sequence Data ; MUTANTS ; Mutation ; MUTATIONS ; national synchrotron light source ; NEOPLASMS ; Phosphorylation ; PHOSPHOTRANSFERASES ; Protein Structure, Tertiary ; Receptor, Fibroblast Growth Factor, Type 2 - chemistry ; Receptor, Fibroblast Growth Factor, Type 2 - genetics ; Receptor, Fibroblast Growth Factor, Type 2 - metabolism ; RECEPTORS ; REGULATIONS ; RESIDUES ; Sequence Alignment ; SIGNALING ; SKELETON ; TYROSINE</subject><ispartof>Molecular Cell, 2007-09, Vol.27 (5), p.717-730</ispartof><rights>2007 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-278759b6e64aab4d0ee6d66a0c9d93654814cae7af2a0cfc81b2ec7bc059ee5e3</citedby><cites>FETCH-LOGICAL-c553t-278759b6e64aab4d0ee6d66a0c9d93654814cae7af2a0cfc81b2ec7bc059ee5e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.molcel.2007.06.028$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17803937$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/930014$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Huaibin</creatorcontrib><creatorcontrib>Ma, Jinghong</creatorcontrib><creatorcontrib>Li, Wanqing</creatorcontrib><creatorcontrib>Eliseenkova, Anna V.</creatorcontrib><creatorcontrib>Xu, Chongfeng</creatorcontrib><creatorcontrib>Neubert, Thomas A.</creatorcontrib><creatorcontrib>Miller, W. Todd</creatorcontrib><creatorcontrib>Mohammadi, Moosa</creatorcontrib><creatorcontrib>Brookhaven National Laboratory (BNL) National Synchrotron Light Source</creatorcontrib><title>A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases</title><title>Molecular Cell</title><addtitle>Mol Cell</addtitle><description>Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory “molecular brake” mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.</description><subject>Amino Acid Sequence</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Activation</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>MATERIALS SCIENCE</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>MUTANTS</subject><subject>Mutation</subject><subject>MUTATIONS</subject><subject>national synchrotron light source</subject><subject>NEOPLASMS</subject><subject>Phosphorylation</subject><subject>PHOSPHOTRANSFERASES</subject><subject>Protein Structure, Tertiary</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - chemistry</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - genetics</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - metabolism</subject><subject>RECEPTORS</subject><subject>REGULATIONS</subject><subject>RESIDUES</subject><subject>Sequence Alignment</subject><subject>SIGNALING</subject><subject>SKELETON</subject><subject>TYROSINE</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1vGyEQRVGj5qP9B1FFL7l5CyzLLpdKTpQvNVWlKj1Tlp21cdfgALbkfx82dpPm0tMg5s2bN-8hdEZJQQkVXxbF0g8GhoIRUhdEFIQ1B-iYEllPOBX83f7NalEdoZMYF4RQXjXyPTqidUNKWdbH6PcUf_cDmPWgA74I-g9g63CaA_5mnY6Ab62bAf4JM-vdWDIwQXxGTE2yG5u22Pe5Y2CVfMAP2-CjdX_n4wd02Oshwsd9PUW_rq8eLm8n9z9u7i6n9xNTVWXKKpu6kq0AwbVueUcARCeEJkZ2shQVbyg3Gmrds_zXm4a2DEzdGlJJgArKU_R1x7tat0voDLgU9KBWwS512CqvrXrbcXauZn6jGJGcsiYTfN4R-JisisYmMHPjnQOTlCxH8zLmfL8k-Mc1xKSWNuYMBu3Ar6MSDSsllSwD-Q5oshsxQP8ihBI1xqcWahefGuNTRCjyrOHTv0e8Du3zer0SspUbC2EUCs5AZ8Oos_P2_xueADmRr38</recordid><startdate>20070907</startdate><enddate>20070907</enddate><creator>Chen, Huaibin</creator><creator>Ma, Jinghong</creator><creator>Li, Wanqing</creator><creator>Eliseenkova, Anna V.</creator><creator>Xu, Chongfeng</creator><creator>Neubert, Thomas A.</creator><creator>Miller, W. Todd</creator><creator>Mohammadi, Moosa</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20070907</creationdate><title>A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases</title><author>Chen, Huaibin ; Ma, Jinghong ; Li, Wanqing ; Eliseenkova, Anna V. ; Xu, Chongfeng ; Neubert, Thomas A. ; Miller, W. Todd ; Mohammadi, Moosa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c553t-278759b6e64aab4d0ee6d66a0c9d93654814cae7af2a0cfc81b2ec7bc059ee5e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Amino Acid Sequence</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallography, X-Ray</topic><topic>Enzyme Activation</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>MATERIALS SCIENCE</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>MUTANTS</topic><topic>Mutation</topic><topic>MUTATIONS</topic><topic>national synchrotron light source</topic><topic>NEOPLASMS</topic><topic>Phosphorylation</topic><topic>PHOSPHOTRANSFERASES</topic><topic>Protein Structure, Tertiary</topic><topic>Receptor, Fibroblast Growth Factor, Type 2 - chemistry</topic><topic>Receptor, Fibroblast Growth Factor, Type 2 - genetics</topic><topic>Receptor, Fibroblast Growth Factor, Type 2 - metabolism</topic><topic>RECEPTORS</topic><topic>REGULATIONS</topic><topic>RESIDUES</topic><topic>Sequence Alignment</topic><topic>SIGNALING</topic><topic>SKELETON</topic><topic>TYROSINE</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Huaibin</creatorcontrib><creatorcontrib>Ma, Jinghong</creatorcontrib><creatorcontrib>Li, Wanqing</creatorcontrib><creatorcontrib>Eliseenkova, Anna V.</creatorcontrib><creatorcontrib>Xu, Chongfeng</creatorcontrib><creatorcontrib>Neubert, Thomas A.</creatorcontrib><creatorcontrib>Miller, W. Todd</creatorcontrib><creatorcontrib>Mohammadi, Moosa</creatorcontrib><creatorcontrib>Brookhaven National Laboratory (BNL) National Synchrotron Light Source</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Huaibin</au><au>Ma, Jinghong</au><au>Li, Wanqing</au><au>Eliseenkova, Anna V.</au><au>Xu, Chongfeng</au><au>Neubert, Thomas A.</au><au>Miller, W. Todd</au><au>Mohammadi, Moosa</au><aucorp>Brookhaven National Laboratory (BNL) National Synchrotron Light Source</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases</atitle><jtitle>Molecular Cell</jtitle><addtitle>Mol Cell</addtitle><date>2007-09-07</date><risdate>2007</risdate><volume>27</volume><issue>5</issue><spage>717</spage><epage>730</epage><pages>717-730</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory “molecular brake” mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17803937</pmid><doi>10.1016/j.molcel.2007.06.028</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-2765 |
| ispartof | Molecular Cell, 2007-09, Vol.27 (5), p.717-730 |
| issn | 1097-2765 1097-4164 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2094128 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence CRYSTAL STRUCTURE Crystallography, X-Ray Enzyme Activation Humans Hydrogen Bonding MATERIALS SCIENCE Models, Molecular Molecular Sequence Data MUTANTS Mutation MUTATIONS national synchrotron light source NEOPLASMS Phosphorylation PHOSPHOTRANSFERASES Protein Structure, Tertiary Receptor, Fibroblast Growth Factor, Type 2 - chemistry Receptor, Fibroblast Growth Factor, Type 2 - genetics Receptor, Fibroblast Growth Factor, Type 2 - metabolism RECEPTORS REGULATIONS RESIDUES Sequence Alignment SIGNALING SKELETON TYROSINE |
| title | A Molecular Brake in the Kinase Hinge Region Regulates the Activity of Receptor Tyrosine Kinases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T16%3A46%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Molecular%20Brake%20in%20the%20Kinase%20Hinge%20Region%20Regulates%20the%20Activity%20of%20Receptor%20Tyrosine%20Kinases&rft.jtitle=Molecular%20Cell&rft.au=Chen,%20Huaibin&rft.aucorp=Brookhaven%20National%20Laboratory%20(BNL)%20National%20Synchrotron%20Light%20Source&rft.date=2007-09-07&rft.volume=27&rft.issue=5&rft.spage=717&rft.epage=730&rft.pages=717-730&rft.issn=1097-2765&rft.eissn=1097-4164&rft_id=info:doi/10.1016/j.molcel.2007.06.028&rft_dat=%3Cproquest_pubme%3E68239192%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=68239192&rft_id=info:pmid/17803937&rft_els_id=S1097276507004406&rfr_iscdi=true |