Leptin receptor (OB-R) signaling: cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization
The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription...
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| Veröffentlicht in: | The Journal of biological chemistry 1997-02, Vol.272 (7), p.4065-4071 |
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| container_title | The Journal of biological chemistry |
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| creator | White, D.W. (Millennium Pharmaceuticals, Cambridge, MA.) Kuropatwinski, K.K Devos, R Baumann, H Tartaglia, L.A |
| description | The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the pretence of excess naturally occurring short form of OB-R |
| doi_str_mv | 10.1074/jbc.272.7.4065 |
| format | Article |
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(Millennium Pharmaceuticals, Cambridge, MA.) ; Kuropatwinski, K.K ; Devos, R ; Baumann, H ; Tartaglia, L.A</creator><creatorcontrib>White, D.W. (Millennium Pharmaceuticals, Cambridge, MA.) ; Kuropatwinski, K.K ; Devos, R ; Baumann, H ; Tartaglia, L.A</creatorcontrib><description>The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the pretence of excess naturally occurring short form of OB-R</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.272.7.4065</identifier><identifier>PMID: 9020115</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Line ; CHIMIORECEPTEUR ; CITOQUINAS ; CITOQUININAS ; COS Cells ; CYTOKINE ; CYTOKININE ; Cytoplasm - metabolism ; EXPRESION GENICA ; EXPRESSION DES GENES ; GENE ; GENERO HUMANO ; GENES ; GENETICA ; GENETIQUE ; GENRE HUMAIN ; HORMONAS ; HORMONE ; MUTACION ; MUTACION INDUCIDA ; Mutagenesis ; MUTANT ; MUTANTES ; MUTATION ; MUTATION PROVOQUEE ; PROTEINAS ; PROTEINE ; QUIMIORECEPTORES ; RECEPTEUR D'HORMONE ; RECEPTORES DE HORMONAS ; Receptors, Cell Surface ; Receptors, Granulocyte Colony-Stimulating Factor - genetics ; Receptors, Granulocyte Colony-Stimulating Factor - metabolism ; Receptors, Leptin ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Signal Transduction ; TRANSCRIPCION ; TRANSCRIPTION</subject><ispartof>The Journal of biological chemistry, 1997-02, Vol.272 (7), p.4065-4071</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9020115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>White, D.W. (Millennium Pharmaceuticals, Cambridge, MA.)</creatorcontrib><creatorcontrib>Kuropatwinski, K.K</creatorcontrib><creatorcontrib>Devos, R</creatorcontrib><creatorcontrib>Baumann, H</creatorcontrib><creatorcontrib>Tartaglia, L.A</creatorcontrib><title>Leptin receptor (OB-R) signaling: cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. However, signaling by full-length OB-R appears to be relatively resistant to dominant negative repression by signaling-incompetent OB-R, suggesting that mechanisms exist to permit signaling by the long form of OB-R even in the pretence of excess naturally occurring short form of OB-R</description><subject>Animals</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Line</subject><subject>CHIMIORECEPTEUR</subject><subject>CITOQUINAS</subject><subject>CITOQUININAS</subject><subject>COS Cells</subject><subject>CYTOKINE</subject><subject>CYTOKININE</subject><subject>Cytoplasm - metabolism</subject><subject>EXPRESION GENICA</subject><subject>EXPRESSION DES GENES</subject><subject>GENE</subject><subject>GENERO HUMANO</subject><subject>GENES</subject><subject>GENETICA</subject><subject>GENETIQUE</subject><subject>GENRE HUMAIN</subject><subject>HORMONAS</subject><subject>HORMONE</subject><subject>MUTACION</subject><subject>MUTACION INDUCIDA</subject><subject>Mutagenesis</subject><subject>MUTANT</subject><subject>MUTANTES</subject><subject>MUTATION</subject><subject>MUTATION PROVOQUEE</subject><subject>PROTEINAS</subject><subject>PROTEINE</subject><subject>QUIMIORECEPTORES</subject><subject>RECEPTEUR D'HORMONE</subject><subject>RECEPTORES DE HORMONAS</subject><subject>Receptors, Cell Surface</subject><subject>Receptors, Granulocyte Colony-Stimulating Factor - genetics</subject><subject>Receptors, Granulocyte Colony-Stimulating Factor - metabolism</subject><subject>Receptors, Leptin</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>TRANSCRIPCION</subject><subject>TRANSCRIPTION</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kM1Lw0AQxRdRaq1ePQhCTqKHxP1Mut60-AWFglrwFnY3k7glydZsotS_3sUW5zDz4P3mHR5CpwQnBGf8eqVNQjOaZAnHqdhDY4KnLGaCvO-jMcaUxJKK6SE68n6Fw3BJRmgkMcWEiDH6nsO6t23UgQnCddHl4i5-uYq8rVpV27a6icymd-ta-caaqHCNCnQz9Kq3LhCRCmvjrQ-iiODLFtAaiMqQ9B_54RoXu9pWroHO_vx9HqODUtUeTnZ3gpYP92-zp3i-eHye3c7jkoq0j7UuBOYcl4YYQQtZcs04I1pQMEobLiEjhQauGANQWOBpllGdliXmMNWpYRN0sc1dd-5zAN_njfUG6lq14AafEyEJZZIH8HwHDrqBIl93tlHdJt81FfyzrV8ql6uqsz5fvsqMp0xi9gvZiHXC</recordid><startdate>19970214</startdate><enddate>19970214</enddate><creator>White, D.W. 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(Millennium Pharmaceuticals, Cambridge, MA.) ; Kuropatwinski, K.K ; Devos, R ; Baumann, H ; Tartaglia, L.A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-f256t-bbd50440fc1c52d9f4b3431b52ecabc49e71dbe4a33eea0508772b6ff04e8b6c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Line</topic><topic>CHIMIORECEPTEUR</topic><topic>CITOQUINAS</topic><topic>CITOQUININAS</topic><topic>COS Cells</topic><topic>CYTOKINE</topic><topic>CYTOKININE</topic><topic>Cytoplasm - metabolism</topic><topic>EXPRESION GENICA</topic><topic>EXPRESSION DES GENES</topic><topic>GENE</topic><topic>GENERO HUMANO</topic><topic>GENES</topic><topic>GENETICA</topic><topic>GENETIQUE</topic><topic>GENRE HUMAIN</topic><topic>HORMONAS</topic><topic>HORMONE</topic><topic>MUTACION</topic><topic>MUTACION INDUCIDA</topic><topic>Mutagenesis</topic><topic>MUTANT</topic><topic>MUTANTES</topic><topic>MUTATION</topic><topic>MUTATION PROVOQUEE</topic><topic>PROTEINAS</topic><topic>PROTEINE</topic><topic>QUIMIORECEPTORES</topic><topic>RECEPTEUR D'HORMONE</topic><topic>RECEPTORES DE HORMONAS</topic><topic>Receptors, Cell Surface</topic><topic>Receptors, Granulocyte Colony-Stimulating Factor - genetics</topic><topic>Receptors, Granulocyte Colony-Stimulating Factor - metabolism</topic><topic>Receptors, Leptin</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>TRANSCRIPCION</topic><topic>TRANSCRIPTION</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>White, D.W. (Millennium Pharmaceuticals, Cambridge, MA.)</creatorcontrib><creatorcontrib>Kuropatwinski, K.K</creatorcontrib><creatorcontrib>Devos, R</creatorcontrib><creatorcontrib>Baumann, H</creatorcontrib><creatorcontrib>Tartaglia, L.A</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Nucleic Acids Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>White, D.W. (Millennium Pharmaceuticals, Cambridge, MA.)</au><au>Kuropatwinski, K.K</au><au>Devos, R</au><au>Baumann, H</au><au>Tartaglia, L.A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Leptin receptor (OB-R) signaling: cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1997-02-14</date><risdate>1997</risdate><volume>272</volume><issue>7</issue><spage>4065</spage><epage>4071</epage><pages>4065-4071</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The leptin receptor (OB-R) mediates the weight regulatory effects of the adipocyte secreted hormone leptin (OB). Previously we have shown that the long form of OB-R, expressed predominantly in the hypothalamus, can mediate ligand-induced activation of signal transducer and activator of transcription factors 1, 3, and 5 and stimulate transcription via interleukin-6 and hematopoietin receptor responsive gene elements. Here we report that deletion and tyrosine substitution mutagenesis of OB-R identifies two distinct regions of the intracellular domain important for signaling. In addition, granulocyte-colony stimulatory factor receptor/OB-R and OB-R/granulocyte-colony stimulatory factor receptor chimeras are signaling competent and provide evidence that aggregation of two OB-R intracellular domains is sufficient for ligand-induced receptor activation. 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| issn | 0021-9258 1083-351X |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line CHIMIORECEPTEUR CITOQUINAS CITOQUININAS COS Cells CYTOKINE CYTOKININE Cytoplasm - metabolism EXPRESION GENICA EXPRESSION DES GENES GENE GENERO HUMANO GENES GENETICA GENETIQUE GENRE HUMAIN HORMONAS HORMONE MUTACION MUTACION INDUCIDA Mutagenesis MUTANT MUTANTES MUTATION MUTATION PROVOQUEE PROTEINAS PROTEINE QUIMIORECEPTORES RECEPTEUR D'HORMONE RECEPTORES DE HORMONAS Receptors, Cell Surface Receptors, Granulocyte Colony-Stimulating Factor - genetics Receptors, Granulocyte Colony-Stimulating Factor - metabolism Receptors, Leptin Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Signal Transduction TRANSCRIPCION TRANSCRIPTION |
| title | Leptin receptor (OB-R) signaling: cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization |
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