Control of the cell morphology and the S phase entry by mitogen-activated protein kinase kinase - A regulatory role of its N-terminal region

The mitogen-activated protein kinase kinase (MAPKK)/MAP kinase (MAPK) casca de plays an important role in the growth control of mammalian cells. We hav e found that expression of constitutively active MAPKK induces rapid morpho logical changes of fibroblastic cells, which are accompanied by disruption of stress fibers and disappearance of focal adhesions. These changes took p lace under the conditions that inhibited cellular Pas function, suggesting a linkage between the MAPK cascade and the control of cell morphology. We f urther show that constitutively active MAPKK can induce expression of endog enous Fos protein, an immediately early gene product, and cause the S phase entry of G(0)-arrested cells. Finally, expression of the N-terminal fragme nt of MAPKK which encompasses the nuclear export signal sequence and the MA PK-binding site blocked both the serum-induced S phase entry of quiescent c ells and the oncogenic Ras induced morphological changes. All these results demonstrate that MAPKK is one of key molecules involved in the control of both cell morphology and cell proliferation and suggest an important role f or the N-terminal region of MAPKK in the regulation of the MAPK signaling.