The protein-tyrosine phosphatase DEP-1 modulates growth factor-stimulated cell migration and cell-matrix adhesion.
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.
Jandt
Enrico
E
Research Unit Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Drackendorfer str 1, D-07747 Jena, Germany.
Denner
Karsten
K
Kovalenko
Marina
M
Ostman
Arne
A
Böhmer
Frank-D
FD
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006133:Growth Substances / Q000378:metabolism*; D015151:Immunoblotting; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
D006133:Growth Substances; D015544:Inositol 1,4,5-Trisphosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D018631:ras Proteins; C098066:Ptprj protein, mouse