Activation of the Hematopoietic Progenitor Kinase-1 (HPK1)-dependent, Stress-activated c-Jun N-terminal Kinase (JNK) Pathway by Transforming Growth Factor β (TGF-β)-activated Kinase (TAK1), a Kinase Mediator of TGF β Signal Transduction*
- From the ‡Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, the ¶Department of Experimental Hematology, Amgen, Inc., Thousand Oaks, California 91320, and the ‖Department of Biology, Amgen, Inc., Boulder, Colorado 80301
Abstract
Transforming growth factor β (TGF-β)-activated kinase (TAK1) is known for its involvement in TGF-β signaling and its ability to activate the p38-mitogen-activated protein kinase (MAPK) pathway. This report shows that TAK1 is also a strong activator of c-Jun N-terminal kinase (JNK). Both the wild-type and a constitutively active mutant of TAK1 stimulated JNK in transient transfection assays. Mitogen-activated protein kinase kinase 4 (MKK4)/stress-activated protein kinase/extracellular 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 kinasedefective mutant of TAK1 effectively suppressed hematopoietic progenitor kinase-1 (HPK1)-induced JNK activity 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 and MLK3 did not inhibit TAK1-induced JNK activity, we conclude that activation of JNK1 by TAK1 is independent of MEKK1 and MLK3. In addition to TAK1, TGF-β also stimulated JNK activity. Taken together, these results identify TAK1 as a regulator in the HPK1 → TAK1 → MKK4/SEK1 → JNK kinase cascade and indicate the involvement of JNK in the TGF-β signaling pathway. Our results also suggest the potential roles of TAK1 not only in the TGF-β pathway but also in the other HPK1/JNK1-mediated pathways.
Footnotes
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↵* This work was supported by National Institutes of Health Grants R01-GM49875 and R01-AI38649 (to T.-H. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ The first two authors contributed equally to this work.
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↵** A Scholar of the Leukemia Society of America. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Baylor College of Medicine, M929, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-4665; Fax: 713-798-3700; E-mail:ttan{at}bcm.tmc.edu.
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↵1 The abbreviations used are: MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; TGF-β, transforming growth factor β; TAK, transforming growth factor β-activated kinase; HPK1, hematopoietic progenitor kinase-1; MEKK1, mitogen-activated protein kinase kinase kinase-1; MLK, mixed lineage kinase; GCK, germinal center kinase; SEK, stress-activated protein kinase/extracellular signal-regulated kinase; ERK, extracellular signal-regulated kinase; GST, glutathioneS-transferase; HA, hemagglutinin; MOPS, 4-morpholinepropanesulfonic acid; PAGE, polyacrylamide gel electrophoresis.
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- Received June 17, 1997.
