['TGFbeta is a potent stimulator of cell growth in cultured rat articular chondrocytes (CRAC). The stimulatory effect is mediated through the immediate induction of c-fos gene by activating ERK of MAPK. The present study was undertaken to investigate the upstream regulators involved in TGFbeta-induced ERK activation in CRAC and to compare the results with the events in HepG2 cells.', 'In vitro kinase and trans-reporting assays showed that TGFbeta preferentially activated ERK and JNK pathways in CRAC and HepG2, respectively. ERK activation in CRAC was selectively inhibited by PD98059, a MEK inhibitor. Overexpression of wild or active forms of MEKK1, the upstream activator of ERK and JNK, decreased the TGFbeta-induced 3TP-luciferase activity in CRAC. In contrast, in HepG2 dominant negative form of MEKK1 or SEK1 ligand-dependent reporter activity was diminished. Transfection of TAK1, another MAPKKK, also positively and negatively regulated 3TP transcriptional activity of HepG2 and CRAC, respectively. Activation of PKA by 8-bromo-cyclic AMP or forskolin, and inhibition of PKC by calphostin C, resulted in a significant decrease in 3TP activity as well as in vitro ERK kinase activity in CRAC.'] Is activation of specific MEK-ERK cascade necessary for TGFbeta signaling and crosstalk with PKA and PKC pathways in cultured rat articular chondrocytes?