The tyrosine phosphatase Shp-2 mediates intracellular signaling initiated by Ret mutants.

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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

D'Alessio A,Califano D,Incoronato M,Santelli G,Florio T,Schettini G,Carlomagno MS,Cerchia L,de Franciscis V

doi

10.1210/en.2003-0620

subject

Has Abstract

pub_date

2003-10-01 00:00:00

pages

4298-305

issue

10

eissn

0013-7227

issn

1945-7170

pii

en.2003-0620

journal_volume

144

pub_type

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