tailieunhanh - Báo cáo khoa học: Induction of uPA gene expression by the blockage of E-cadherin via Src- and Shc-dependent Erk signaling

Loss of E-cadherin-mediated cell–cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive, metastatic tumor, a rate-limiting step in the progression from adenoma to carcinoma in vivo. A soluble E-cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell–cell adhe-sion and to drive cell invasion in a dominant-interfering manner. | ỊFEBS Journal Induction of uPA gene expression by the blockage of E-cadherin via Src- and Shc-dependent Erk signaling Sandra Kleiner Amir Faisal and Yoshikuni Nagamine Friedrich Miescher Institute for BiomedicalResearch Basel Switzerland Keywords E-cadherin Shc signalling Src uPA Correspondence Y. Nagamine Friedrich Miescher Institute for Biomedical Research Maulbeerstrasse 66 CH-4058 Basel Switzerland Fax 41 61 697 3976 Tel 41 61 697 6669 E-mail Present address Cancer Research UK London Research Institute 44 Lincoln s Inn Fields London WC2A3PX UK Received 26 July 2006 revised 25 October 2006 accepted 7 November 2006 doi Loss of E-cadherin-mediated cell-cell adhesion and expression of proteolytic enzymes characterize the transition from benign lesions to invasive metastatic tumor a rate-limiting step in the progression from adenoma to carcinoma in vivo. A soluble E-cadherin fragment found recently in the serum and urine of cancer patients has been shown to disrupt cell-cell adhesion and to drive cell invasion in a dominant-interfering manner. Physical disruption of cell-cell adhesion can be mimicked by the function-blocking antibody Decma. We have shown previously in MCF7 and T47D cells that urokinase-type plasminogen activator uPA activity is up-regulated upon disruption of E-cadherin-dependent cell-cell adhesion. We explored the underlying molecular mechanisms and found that blockage of E-cadherin by Decma elicits a signaling pathway downstream of E-cadherin that leads to Src-dependent Shc and extracellular regulated kinase Erk activation and results in uPA gene activation. siRNA-mediated knockdown of endogenous Src-homology collagen protein Shc and subsequent expression of single Shc isoforms revealed that p46Shc and p52Shc but not p66Shc were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma-induced Erk activation. This report describes that disruption of .