Role of the ERK MAP Kinase Cascade in the Regulation of Cell Proliferation and Differentiation.

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(1) Mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, . In growth-arrested Swiss 3T3 cells, MAP kinases are mainly cytoplasmic. Subsequent to mitogenic stimulation by serum, MAP kinases are activated and translocated into nucleus. This translocation is rapid (seen in 10 min), persistent (up to 6 h), reversible (by removal of stimulus) and apparently coupled to the mitogenic potential.(2) HGF and PMA markedly induced the spreading, dissociation and scattering of MDCK cells. In all these agent-stimulated cells, rapid activation of Raf-1, MAP kinase/ERK kinase (MEK), 41-/43-kDa MAP kinases and p90^<rsk> was commonly observed. Pretreatment of MDCK cells with PD98059, a specific inhibitor of MEK,selectively inhibited the HGF- and PMA--stimulated activities of MEK,41-/43-kDa MAP kinases and p90r^<sk> in a dose dependent manner. Importantly, HGF- and PMA-induced scattering of MDCK ce … More lls was inhibited at doses of AMPC similar to those that gave comparable levels of inhibition of the activities of MEK,41-/43-kDa MAP kinases and p90^<rsk>. These results suggest that activation of the 41-/43-kDa MAP kinase signaling pathway is required for the motility response of MDCKcells induced by agents such as HGF and PMA.(3) BMP-2 induced morphological changes in PC12 cells with the concomitant expression of three neurofilament proteins. Unlike NGF and bFGF however, BMP-2 failed to induce the activation of either 41- and 43-kDa MAP kinases or the (MEK.Also, BMP-2 did not induce the expression of the c-fos gene in PC12 cells. Activin A was also capable of inducing the neuronal differentiation of PC12 cells without activating MAP kinases and MEK.These findings show a clear dissociation between the requirement for the activation of the MAP kinase cascade and the ability of BMP-2 and activin A to induce PC12 cell neuronal differentiation. In addition, these results suggest that the activation of MAP kinases and MEK is not an absolute requirement for PC12 cell differentiation. Less