Modulation of the ERK pathway of signal transduction by cysteine proteinase inhibitors

Cell proliferation requires the coordinate synthesis and degradation of man y proteins. In addition to the well-characterized involvement of the protea some in the degradation of several cell cycle-regulated proteins, it has be en established that cysteine proteinases are also involved in the control o f cell proliferation, but their role is currently not understood. By using both synthetic cysteine proteinase inhibitors and overexpression of T-kinin ogen (T-KG), a physiologically relevant cysteine proteinase inhibitor, we s how that inhibition of cysteine proteinases results in a severe inhibition of the ERK pathway of signal transduction. Mechanistically, this effect app ears to be the result of stabilization of the ERK phosphatase MKP-1, which leads to an enhanced dephosphorylation (and hence inactivation) of ERK mole cules. These results are specific to cysteine proteinase inhibitors and are not observed when either serine proteinases or the proteasome are inhibite d. We hypothesize that inhibition of cysteine proteinases in vivo leads to a dysregulation of the ERK pathway, which results in an inability of the ce ll to transmit to the nucleus the signals generated by the presence of grow th factors, thus resulting in loss of cell proliferation. (C) 2000 Wiley-Li ss. Inc.