ACTIVATION OF THE HEMATOPOIETIC PROGENITOR KINASE-1 (HPK1)-DEPENDENT,STRESS-ACTIVATED C-JUN N-TERMINAL KINASE (JNK) PATHWAY BY TRANSFORMING-GROWTH-FACTOR-BETA (TGF-BETA)-ACTIVATED KINASE (TAK1), A KINASE MEDIATOR OF TGF-BETA SIGNAL-TRANSDUCTION

Transforming growth factor beta (TGF-beta)-activated kinase (TAK1) is known for its involvement in TGF-beta signaling and its ability to act ivate the p38-mitogen-activated protein kinase (MAPK) pathway, This re port shows that TAK1 is also a strong activator of c-Jun N-terminal ki nase (JNK). Both the wild-type and a constitutively active mutant of T AK1 stimulated JNK in transient transfection assays, Mitogen-activated protein kinase kinase 4 (MKK4)/stress-activated protein kinase/extrac ellular signal-regulated kinase (SEK1), a dual-specificity kinase that phosphorylates and activates JNK, synergized with TAK1 in activating JNK. Conversely, a dominant-negative (MKK4/SEK1 mutant inhibited TAK1- induced JNK activation. A kinase-defective mutant of TAK1 effectively suppressed hematopoietic progenitor kinase-1 (HPK1)-induced JNK activi ty but had little effect on germinal center kinase activation of JNK. There are two additional MAPK kinase kinases, MEKK1 and mixed lineage kinase 3 (MLK3), that are also downstream of HPK1 and upstream of MKK4 /SEK mutant, However, because the dominant-negative mutants of MEKK1 a nd MLK3 did not inhibit TAK1-induced JNK activity, we conclude that ac tivation of JNK1 by TAK1 is independent of MEKK1 and MLK3. In addition to TAK1, TGF-beta also stimulated JNK activity, Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SE K1 --> JNK kinase cascade and indicate the involvement of JNK in the T GF-beta signaling pathway, Our results also suggest the potential role s of TAK1 not only in the TGF-beta pathway but also in the other HPK1/ JNK1-mediated pathways.