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

摘要: Deregulation of receptor tyrosine kinases (RTK) contributes to the initiation and progression intestinal-derived epithelial cancers, including colorectal cancer (CRC). However, roles proximal signaling molecules engaged by RTKs in different oncogenic functions CRC remain unclear. Herein, functional impact expressing variant forms Met (Tpr-Met) that selectively recruit adaptor proteins Grb2 or Shc was investigated a model derived from normal intestinal cells (IEC-6). An RNA interference (RNAi) approach used define requirement Tpr-Met-transformed IEC-6 cells. Since couple activation Ras/MEK/Erk PI3K/Akt pathways, Erk Akt phosphorylation/activation states were monitored transformed cells, pharmacological employed provide insights into these pathways processes evoked activated Met, downstream Shc. We show, for first time, constitutive either signals promotes morphological transformation associated with down-regulation E-cadherin, as well increased cell growth, loss growth contact inhibition, anchorage-independent resistance serum deprivation anoikis. Oncogenic revealed induce transformation, E-cadherin down-regulation, protection against anoikis mechanisms dependent on Grb2, while shown be partly required enhanced growth. The coupling sustained engagement IECs, trigger negative feedback, limiting extent pathways. Nonetheless, alterations induced Tpr-Met, signals, blocked MEK, but not PI3K, inhibitors Tpr-Met nearly abolished co-treatment both inhibitors. Overall, results identify central effectors Met-driven epithelial-derived cancers. Notably, they suggest may represent promising target design novel therapies.