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
Hauptverfasser: D’Alessio, A, Califano, D, Incoronato, M, Santelli, G, Florio, T, Schettini, G, Carlomagno, M. S, Cerchia, L, de Franciscis, V
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container_issue 10
container_start_page 4298
container_title Endocrinology (Philadelphia)
container_volume 144
creator D’Alessio, A
Califano, D
Incoronato, M
Santelli, G
Florio, T
Schettini, G
Carlomagno, M. S
Cerchia, L
de Franciscis, V
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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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. 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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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