Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Cells Tissues Organs 2007;185:180–190 DOI: 10.1159/000101319 Signaling Pathways Involved in Collagen-Induced Disruption of the E-Cadherin Complex during Epithelial-Mesenchymal Transition Yukiko Imamichi Andre Menke Department of Internal Medicine I, University of Ulm, Ulm, Germany Introduction Although there is accumulating evidence that the mi- croenvironment plays an important role in establishing and maintaining epithelial cell differentiation and polar- ity, the fundamental mechanisms involved in these pro- cesses are not completely characterized. Differentiated epithelial cells have contact with the basal lamina, which consists mainly of collagen type IV, laminin and proteo- glycans [Hay, 1993]. In contrast, many epithelial tumors contain increased amounts of extracellular matrix (ECM). As a consequence, the tumor cells have contact with ad- ditional ECM proteins, such as collagen types I and III, Key Words E-cadherin adhesion complex  Epithelial-mesenchymal transition   -Catenin phosphorylation  Collagen type I  Collagen type III  Focal adhesion kinase  PTEN  Metastasis  Pancreatic cancer Abstract There is substantial interest in the influence of the microen- vironment on tumor cells. Cell-cell as well as cell-matrix in- teractions have been correlated with the control of different processes such as tumor cell proliferation, differentiation, survival and migration. In this review, we focus on the influ- ence of collagen types I and III expressed in carcinomata on the E-cadherin-mediated adhesion between epithelial tu- mor cells. Recently published studies described the ability of fibrillar collagen to reduce E-cadherin gene expression and to induce disruption of the E-cadherin adhesion complex. The reduced cellular adhesion influences tissue integrity and has been correlated with elevated cell migration and invasion of different carcinoma cells. Altered tyrosine phos- phorylation of the intracellular, cadherin-associated caten- ins was identified as an important regulator of collagen-in- duced disassembly of the E-cadherin adhesion complex. The molecular mechanisms involved in collagen-induced cell transformation include activation of integrins, activation and translocation of the focal adhesion kinase to the E-cad- herin/catenin complex as well as inhibition of the phospha- tase PTEN. Copyright © 2007 S. Karger AG, Basel Dr. Andre Menke Department of Internal Medicine I, University of Ulm DE–89070 Ulm (Germany) Tel. +49 731 500 44678, Fax +49 731 500 45216 E-Mail andre.menke@uni-ulm.de © 2007 S. Karger AG, Basel 1422–6405/07/1853–0180$23.50/0 Accessible online at: www.karger.com/cto Abbreviations used in this paper ECM extracellular matrix EMT epithelial-mesenchymal transition ERK extracellular signal-regulated kinase FAK focal adhesion kinase FRNK FAK-related nonkinase MAPK mitogen-activated protein kinase PI3K phosphatidylinositol 3-kinase PTEN phosphatase and tensin homolog TCP tissue culture plastic TGF- transforming growth factor- SIP1 Smad-interacting protein 1