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 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 uPAgene activation. siRNA-mediated knockdown of endogenous Src-homology collagen protein (Shc) and subsequent expression of single Shc isoforms revealed that p46(Shc) and p52(Shc) but not p66(Shc) were able to mediate Erk activation. A parallel pathway involving PI3K contributed partially to Decma-induced Erk activation. This report describes that disruption of E-cadherin-dependent cell-cell adhesion induces intracellular signaling with the potential to enhance tumorigenesis and, thus, offers new insights into the pathophysiological mechanisms of tumor development.
Kleiner
Sandra
S
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Faisal
Amir
A
Nagamine
Yoshikuni
Y
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015820:Cadherins / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D015820:Cadherins; D034741:RNA, Small Interfering; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator