Integrin-mediated differentiation of a pancreatic carcinoma cell line is independent of FAK or MAPK activation levels.
BACKGROUND
The extracellular matrix (ECM) plays a salient role for proliferation and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression and the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas.


OBJECTIVE
To examine the role of integrins and related signaling events for differentiation.


RESULTS
We established an in vitro model for ECM-induced differentiation of poorly differentiated pancreatic carcinoma cells and found that a specific pattern of ECM proteins resembling basal laminas (matrigel) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta1- and beta4-integrins are required for cellular differentiation. Integrin-associated signaling events include activation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs). However, beta1- and beta4-integrin-mediated differentiation of PaTu-II cells was independent from FAK, ERK, and JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a reduction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel.


CONCLUSIONS
The integrin-mediated differentiation of PaTu-II cells is regulated and maintained through FAK- and MAPK-independent signal transduction pathways.
Stagge
V
V
Department of Internal Medicine I, University of Ulm, Germany.
Seufferlein
T
T
Duerschmied
D
D
Dürschmied
D
D
Menke
A
A
Adler
G
G
Beil
M
M
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002454:Cell Differentiation; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020287:In Situ Nick-End Labeling; D019012:Integrin beta1 / Q000502:physiology; D039663:Integrin beta4; D016023:Integrins / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D019012:Integrin beta1; D039663:Integrin beta4; D016023:Integrins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases