The Tyrosine Phosphatase Shp-2 Mediates Intracellular Signaling Initiated by Ret Mutants
The Src homology 2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways in...
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Veröffentlicht in: | Endocrinology (Philadelphia) 2003-10, Vol.144 (10), p.4298-4305 |
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description | The Src homology 2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions. These mutations convert the receptor tyrosine kinase, Ret, into a dominant transforming protein and induce constitutive activation of its intrinsic tyrosine kinase activity leading to congenital and sporadic cancers in neuroendocrine organs. Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles. Furthermore, we show that Shp-2 activity is required for RetM918T-induced Akt activation. The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B. |
doi_str_mv | 10.1210/en.2003-0620 |
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S ; Cerchia, L ; de Franciscis, V</creator><creatorcontrib>D’Alessio, A ; Califano, D ; Incoronato, M ; Santelli, G ; Florio, T ; Schettini, G ; Carlomagno, M. S ; Cerchia, L ; de Franciscis, V</creatorcontrib><description>The Src homology 2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions. These mutations convert the receptor tyrosine kinase, Ret, into a dominant transforming protein and induce constitutive activation of its intrinsic tyrosine kinase activity leading to congenital and sporadic cancers in neuroendocrine organs. Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles. Furthermore, we show that Shp-2 activity is required for RetM918T-induced Akt activation. The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2003-0620</identifier><identifier>PMID: 12959980</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Bethesda, MD: Endocrine Society</publisher><subject>AKT protein ; Animals ; Biological and medical sciences ; Cell activation ; Cell differentiation ; Cell Differentiation - physiology ; Cell Line ; Cell proliferation ; Cell Survival - physiology ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Glial Cell Line-Derived Neurotrophic Factor ; Homology ; Intracellular ; Intracellular Membranes - physiology ; Intracellular Signaling Peptides and Proteins ; Intracellular signalling ; Kinases ; Methionine ; Multiple endocrine neoplasia ; Mutants ; Mutation - physiology ; Nerve Growth Factors - metabolism ; Oncogene Proteins - genetics ; Oncogene Proteins - metabolism ; PC12 Cells - pathology ; Phosphatase ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases - metabolism ; Protein-tyrosine kinase receptors ; Protein-tyrosine-phosphatase ; Proto-Oncogene Proteins c-ret ; Rats ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptors ; Ret protein ; SHP-2 protein ; Signal Transduction - physiology ; Tyrosine ; Vertebrates: endocrinology</subject><ispartof>Endocrinology (Philadelphia), 2003-10, Vol.144 (10), p.4298-4305</ispartof><rights>Copyright © 2003 by The Endocrine Society 2003</rights><rights>2004 INIST-CNRS</rights><rights>Copyright © 2003 by The Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-2dbc29f3005359c352894397b8261cd5124664d57498286645a28ffa4382a6883</citedby><cites>FETCH-LOGICAL-c459t-2dbc29f3005359c352894397b8261cd5124664d57498286645a28ffa4382a6883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15149551$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12959980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>D’Alessio, A</creatorcontrib><creatorcontrib>Califano, D</creatorcontrib><creatorcontrib>Incoronato, M</creatorcontrib><creatorcontrib>Santelli, G</creatorcontrib><creatorcontrib>Florio, T</creatorcontrib><creatorcontrib>Schettini, G</creatorcontrib><creatorcontrib>Carlomagno, M. S</creatorcontrib><creatorcontrib>Cerchia, L</creatorcontrib><creatorcontrib>de Franciscis, V</creatorcontrib><title>The Tyrosine Phosphatase Shp-2 Mediates Intracellular Signaling Initiated by Ret Mutants</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>The Src homology 2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions. These mutations convert the receptor tyrosine kinase, Ret, into a dominant transforming protein and induce constitutive activation of its intrinsic tyrosine kinase activity leading to congenital and sporadic cancers in neuroendocrine organs. Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles. Furthermore, we show that Shp-2 activity is required for RetM918T-induced Akt activation. The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B.</description><subject>AKT protein</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell activation</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Line</subject><subject>Cell proliferation</subject><subject>Cell Survival - physiology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Glial Cell Line-Derived Neurotrophic Factor</subject><subject>Homology</subject><subject>Intracellular</subject><subject>Intracellular Membranes - physiology</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Intracellular signalling</subject><subject>Kinases</subject><subject>Methionine</subject><subject>Multiple endocrine neoplasia</subject><subject>Mutants</subject><subject>Mutation - physiology</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Oncogene Proteins - genetics</subject><subject>Oncogene Proteins - metabolism</subject><subject>PC12 Cells - pathology</subject><subject>Phosphatase</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11</subject><subject>Protein Tyrosine Phosphatases - metabolism</subject><subject>Protein-tyrosine kinase receptors</subject><subject>Protein-tyrosine-phosphatase</subject><subject>Proto-Oncogene Proteins c-ret</subject><subject>Rats</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Receptors</subject><subject>Ret protein</subject><subject>SHP-2 protein</subject><subject>Signal Transduction - physiology</subject><subject>Tyrosine</subject><subject>Vertebrates: endocrinology</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc9LHDEUx0Op6NZ667kESu3Fsfk5kxyL2FZQlLqF3kI2k3FHZjNjXuaw_70Zd2Ch6CnJ48P7vvcJQp8oOaeMku8-nDNCeEFKRt6hBdVCFhWtyHu0IITyomKsOkIfAB7zUwjBD9ERZVpqrcgC_VuuPV5uYw9t8Phu3cOwtsmCx_froWD4xtetTR7wVUjROt91Y2cjvm8fgu3a8JDrbZqIGq-2-I9P-GZMNiT4iA4a24E_mc9j9Pfn5fLid3F9--vq4sd14YTUqWD1yjHdcEIkl9pxyZQWXFcrxUrqakmZKEtRy0poxVS-SstU01jBFbOlUvwYne76DrF_Gj0ks2lhmtMG349gKl6qUgiSwS__gY_9GPMWYDjlOb5UkmbqbEe5rASib8wQ242NW0OJmXwbH8zk20y-M_55bjquNr7ew7PgDHydAQvOdk20wbWw5yQVWr7kfttx_Ti8FVnMkXxH-lD3LuZvG6IH2G_z6qDPpXuh9A</recordid><startdate>20031001</startdate><enddate>20031001</enddate><creator>D’Alessio, A</creator><creator>Califano, D</creator><creator>Incoronato, M</creator><creator>Santelli, G</creator><creator>Florio, T</creator><creator>Schettini, G</creator><creator>Carlomagno, M. 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S</au><au>Cerchia, L</au><au>de Franciscis, V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Tyrosine Phosphatase Shp-2 Mediates Intracellular Signaling Initiated by Ret Mutants</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2003-10-01</date><risdate>2003</risdate><volume>144</volume><issue>10</issue><spage>4298</spage><epage>4305</epage><pages>4298-4305</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><abstract>The Src homology 2-containing tyrosine phosphatase, Shp-2, is a crucial enzyme that mediates intracellular signaling and is implicated in cell proliferation and differentiation. Here we investigated the involvement of the Shp-2 tyrosine phosphatase in determining the downstream signaling pathways initiated by the Ret oncogene, carrying either the cysteine 634 to tyrosine or the methionine 918 to threonine substitutions. These mutations convert the receptor tyrosine kinase, Ret, into a dominant transforming protein and induce constitutive activation of its intrinsic tyrosine kinase activity leading to congenital and sporadic cancers in neuroendocrine organs. Using the PC12, rat pheochromocytoma cell line, as model system, we show that Shp-2 mediates immediate-early gene expression if induced by either of the mutant alleles. Furthermore, we show that Shp-2 activity is required for RetM918T-induced Akt activation. The results indicate that Shp-2 is a downstream mediator of the mutated receptors RetC634Y and RetM918T, thus suggesting that it may act as a limiting factor in Ret-associated endocrine tumors, in the neoplastic syndromes multiple endocrine neoplasia types 2A and 2B.</abstract><cop>Bethesda, MD</cop><pub>Endocrine Society</pub><pmid>12959980</pmid><doi>10.1210/en.2003-0620</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals |
subjects | AKT protein Animals Biological and medical sciences Cell activation Cell differentiation Cell Differentiation - physiology Cell Line Cell proliferation Cell Survival - physiology Fundamental and applied biological sciences. Psychology Gene expression Glial Cell Line-Derived Neurotrophic Factor Homology Intracellular Intracellular Membranes - physiology Intracellular Signaling Peptides and Proteins Intracellular signalling Kinases Methionine Multiple endocrine neoplasia Mutants Mutation - physiology Nerve Growth Factors - metabolism Oncogene Proteins - genetics Oncogene Proteins - metabolism PC12 Cells - pathology Phosphatase Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatases - metabolism Protein-tyrosine kinase receptors Protein-tyrosine-phosphatase Proto-Oncogene Proteins c-ret Rats Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptors Ret protein SHP-2 protein Signal Transduction - physiology Tyrosine Vertebrates: endocrinology |
title | The Tyrosine Phosphatase Shp-2 Mediates Intracellular Signaling Initiated by Ret Mutants |
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