Integrin-mediated differentiation of a pancreatic carcinoma cell line is independent of FAK or MAPK activation levels

Introduction: The extracellular matrix (ECM) plays a salient role for proli feration and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression an d the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas. Aims: To examine the role of integrins and related signaling events for dif ferentiation. Methodology and Results: We established an in vitro model for ECM-induced d ifferentiation of poorly differentiated pancreatic carcinoma cells and foun d that a specific pattern of ECM proteins resembling basal laminas (matrige l) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta (1)- and beta (4)-integrins are required for cellular differentiation. Integrin-associated signaling events include act ivation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and e -Jun NH2-terminal kinases (JNKs). However, beta (1)- and beta (4)-integrin- mediated differentiation of PaTu-II cells was independent from FAK, ERK, an d JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a red uction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel. Conclusion: The integrin-mediated differentiation of PaTu-II cells is regul ated and maintained through FAK- and MAPK-independent signal transduction p athways.