The protein-tyrosine phosphatase DEP-1 modulates growth factor-stimulated cell migration and cell-matrix adhesion
2003 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 27, 4175-4185 p.Article in journal (Refereed) Published
Density-enhanced protein-tyrosine phosphatase-1 (DEP-1 also CD148) is a transmembrane molecule with a single intracellular PTP domain. It has recently been proposed to function as a tumor suppressor. We have previously shown that DEP-1 dephosphorylates the activated platelet-derived growth factor (PDGF) beta-receptor in a site-selective manner (Kovalenko et al. (2000). J. Biol. Chem. 275, 16219-16226). We analysed cell lines with inducible DEP-1 expression for cellular functions of DEP-1. Several aspects of PDGFbeta-receptor signaling were negatively affected by DEP-1 expression. These include PDGF-stimulated activation of inositol trisphosphate formation, Erk1/2, p21Ras, and Src. Activation of receptor-associated phosphoinositide-3 kinase activity and of Akt/PKB were weakly attenuated at early time points of stimulation. Inhibition of PDGF-stimulated signaling depended on DEP-1 catalytic activity. Importantly, DEP-1 inhibited PDGF-stimulated cell migration. The catalytically inactive DEP-1 C1239S variant enhanced cell migration and PDGF-stimulated Erk1/2 activation, suggesting a dominant negative interference with endogenous DEP-1. In contrast to cell migration, cell-substrate adhesion was promoted by active DEP-1 and delayed or suppressed by DEP-1 C1239S, correlating with positive effects of DEP-1 on adhesion-stimulated Src kinase. We propose that negative regulation of growth-factor stimulated cell migration and promotion of cell-matrix adhesion may be related to the function of DEP-1 as tumor suppressor.
Place, publisher, year, edition, pages
2003. Vol. 22, no 27, 4175-4185 p.
1-Phosphatidylinositol 3-Kinase/metabolism, 3T3 Cells, Animals, Cell Adhesion, Cell Division, Cell Movement, Dose-Response Relationship; Drug, Enzyme Activation, Gene Expression Regulation, Genetic Vectors, Growth Substances/*metabolism, Immunoblotting, Inositol 1;4;5-Trisphosphate/metabolism, Mice, Mitogen-Activated Protein Kinase 1/metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases/metabolism, Mutation, Platelet-Derived Growth Factor/metabolism, Protein-Serine-Threonine Kinases, Protein-Tyrosine-Phosphatase/metabolism/*physiology, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Signal Transduction, Time Factors, Transfection, ras Proteins/metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10674DOI: 10.1038/sj.onc.1206652PubMedID: 12833140OAI: oai:DiVA.org:uu-10674DiVA: diva2:38442