Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functionsReportar como inadecuado

Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Cancer

, 14:240

Cell and molecular biology


BackgroundDeregulation of receptor tyrosine kinases RTK contributes to the initiation and progression of intestinal-derived epithelial cancers, including colorectal cancer CRC. However, the roles of the proximal signaling molecules engaged by RTKs in different oncogenic functions of CRC remain unclear.

MethodsHerein, the functional impact of expressing variant forms of the oncogenic Met receptor Tpr-Met that selectively recruit the adaptor proteins Grb2 or Shc was investigated in a model derived from normal intestinal epithelial cells IEC-6. An RNA interference RNAi approach was used to define the requirement of Grb2 or Shc in Tpr-Met-transformed IEC-6 cells. Since Grb2 and Shc couple RTKs to the activation of the Ras-MEK-Erk and PI3K-Akt pathways, Erk and Akt phosphorylation-activation states were monitored in transformed IEC-6 cells, and a pharmacological approach was employed to provide insights into the roles of these pathways in oncogenic processes evoked by activated Met, and downstream of Grb2 and Shc.

ResultsWe show, for the first time, that constitutive activation of either Grb2 or Shc signals in IEC-6 cells, promotes morphological transformation associated with down-regulation of E-cadherin, as well as increased cell growth, loss of growth contact inhibition, anchorage-independent growth, and resistance to serum deprivation and anoikis. Oncogenic activation of Met was revealed to induce morphological transformation, E-cadherin down-regulation, and protection against anoikis by mechanisms dependent on Grb2, while Shc was shown to be partly required for enhanced cell growth. The coupling of activated Met to the Ras-MEK-Erk and PI3K-Akt pathways, and the sustained engagement of Grb2 or Shc in IECs, was shown to trigger negative feedback, limiting the extent of activation of these pathways. Nonetheless, morphological alterations and E-cadherin down-regulation induced by the oncogenic Tpr-Met, and by Grb2 or Shc signals, were blocked by MEK, but not PI3K, inhibitors while the enhanced growth and resistance to anoikis induced by Tpr-Met were nearly abolished by co-treatment with both inhibitors.

ConclusionOverall, these results identify Grb2 and Shc as central signaling effectors of Met-driven progression of intestinal epithelial-derived cancers. Notably, they suggest that Grb2 may represent a promising target for the design of novel CRC therapies.

KeywordsReceptor tyrosine kinase Grb2 Shc Met Intestinal epithelial cell Transformation Proliferation Anoikis MAPK PI3K Colorectal cancer Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-240 contains supplementary material, which is available to authorized users.

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Autor: Véronique Pomerleau - Mélissa Landry - Jimmy Bernier - Pierre H Vachon - Caroline Saucier


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