Role of MAP kinase cascades in the regulation of diverse cellular functions

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1. We have examined a possible molecular mechanism through which nuclear translocation and retention of ERK-MAP kinases is regulated. A novel 26-kD protein (p26) which contains a SH3 domain at the N-terminus and three ankyrin repeat sequences at the C-terminus has been identified as a candidate molecule which is involved in the regulation of nuclear translocation/retention of ERK-MAP kinases. Overexpression of p26 suppresses the HGF-induced nuclear localization/retention of ERK-MAP kinases in MDCK cells, while siRNA-mediated knockdown of p26 enhances it. p26 interact specifically with a novel 120-kDa protein (p120), and this interaction is suppressed by the phosphorylation of p26 by p90^<rsk>, an effector molecule downstream of the ERK-MAP kinases. These results suggest that nuclear translocation/retention of ERK-MAP kinases is regulated by the ERK-MAP kinase signaling pathway by itself.2. A novel GDP/GTP exchanger of RhoA, GEF-H1, has been shown to be a physiological substrate of ERK- … More MAP kinases. Expression of GEF-H1 is up-regulated by the ERK MAP kinase pathway. Phosphorylation of Thr^<678> by ERK-MAP kinases induces the activation of GEF-H1 thereby activates RhoA, whereas it induces the inhibition of Rac1. Furthermore, siRNA-mediated knock down of GEF-H1 enhances the cell motility response. These results suggest that GEF-H1 is involved in the ERK-MAF kinase pathway-mediated cell motility response.3. c-Jun N-Terminal Kinase (JNK) has been shown to be involved in the regulation of cytokinesis. JNK phosphorylates keratin 8 to induce the relaxation of keratin filaments, which appear to be one of the prerequisites for cells to undergo cytokinesis.4. Combination of 50 μM PD98059 and a low concentration (3 nM) of vincristin induces marked apoptotic cell death response in G_2/M-phase-arrested T24 cells, but not in G_1-/S-phase-arrested cells. Under such conditions, accumulation of cyclinB, Plk1and Aurora-B has been observed. These results suggest that ERK-MAP Kinase pathway is involved in the regulation of spindle check point. Less