Molecular mechanisms and their significance of protein phosphatase families which control the network-system of signal transduction

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1.Using tautomycetin, a novel inhibitor of PP1, we found that PP1 activates Raf-1, resulting in activation of the ERK pathway.2.Expression of C-terminal region-deleted mutant of NIPP1 (NIPP-1-ΔC) induced arrest of the cell cycle and apoptosis. In experiments with a reporter gene, NIPP1-ΔC suppressed splicing of pre-mRNA and decreased level of matured mRNA.3.The PP1α-depleted HeLa cells rounded up and showed increased cell death, indicating that PP1α is essential for cell proliferation.4.Scid and nude mice inoculated with PTPεC-expresser-M1 cells (M1εC) showed significantly prolonged survival time compared with parent M 1 cells.5.Serine-446 in the C-terminal stretch of MKP-7, a novel JNK phosphatase, can be phosphorylated by activated ERK. This phosphorylation stabilized MKP-7 from ubiquitine-dependent degradation. These results strongly suggest that activation of the ERK pathway blocks JNK activation through stabilization of MKP-7 by phosphorylation.6.Forced expression of a novel DSP,LDP-3, in COS-7 cells rathor enhanced activation of JNK and p38.These results demonstrate crucial involvement of protein phosphatases in signal transduction under various conditions including cell proliferation, the cell cycle, cancer, apoptosis, and stress.