The epithelial morphology is defined by the presence of epithelial junctional complexes of desmosomes, adherens junctions and tight junctions that mediate cell-cell adhesion. Tight and adherens junctions are connected to well organized network of actin cytoskeleton underneath plasma membrane forming belt-like actin rings. During epithelial-mesenchymal transition (EMT) cells lose epithelial polarity, scatter and gain increased autonomous mesenchymal-like migratory phenotype. This change includes the remodeling of cytoskeleton, disruption of cell-cell adhesions and change in cellular morphology with concomitant alterations in gene expression program. The ERK pathway, comprised of protein kinases Raf, MEK and ERK and its downstream target RSK, plays important role in epithelial-mesenchymal transition. The activation of the ERK pathway and protein kinase RSK is sufficient to induce epithelial-mesenchymal transition in many cell types.
To study EMT we used MDCK cells expressing conditionally active Raf-1. We observed that early phase of EMT consists of two sequential steps. Initially, the ERK pathway activation induces loss of apical-basolateral polarity with simultaneous cell flattening and increase in cell area. The loss of apical-basal polarity is followed by the weakening of adherens junctions and cell scattering. Interfering with the function of ERK and RSK showed that ERK primarily regulates loss of apical-basal polarity while RSK primarily regulates cell scattering. Thus, it appears that during epithelial – mesenchymal transition ERK and RSK have specific functions and define two regulatory subprograms that act in sequence. Coordinated execution of these subprograms in time generates complex biological response, epithelial-mesenchymal transition.
Support: Czech Science Foundation grant 204/09/0614, EUFP7 Marie Curie IRG grant 231086