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Science 295 (5558): 1291-1294

Copyright © 2002 by the American Association for the Advancement of Science

MAPKK-Independent Activation of p38alpha Mediated by TAB1-Dependent Autophosphorylation of p38alpha

Baoxue Ge,1 Hermann Gram,2 Franco Di Padova,2 Betty Huang,3 Liguo New,1 Richard J. Ulevitch,1 Ying Luo,34 Jiahuai Han1*

Phosphorylation of mitogen-activated protein kinases (MAPKs) on specific tyrosine and threonine sites by MAP kinase kinases (MAPKKs) is thought to be the sole activation mechanism. Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta -activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha . We detected formation of a TRAF6-TAB1-p38alpha complex and showed stimulus-specific TAB1-dependent and TAB1-independent p38alpha activation. These findings suggest that alternative activation pathways contribute to the biological responses of p38alpha to various stimuli.

1 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Novartis Pharma AG, CH-4002, Basel, Switzerland.
3 Rigel, Inc., South San Francisco, CA 94080, USA.
4 Shanghai Genomics, Inc., Shanghai, China.
*   To whom correspondence should be addressed. E-mail: jhan{at}

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MKK3 and -6-dependent activation of p38{alpha} MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation.
Q. Wang, M. Yerukhimovich, W. A. Gaarde, I. J. Popoff, and C. M. Doerschuk (2005)
Am J Physiol Lung Cell Mol Physiol 288, L359-L369
   Abstract »    Full Text »    PDF »
The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death.
J. Cao, J. I. Viholainen, C. Dart, H. K. Warwick, M. L. Leyland, and M. J. Courtney (2005)
J. Cell Biol. 168, 117-126
   Abstract »    Full Text »    PDF »
Toll-like Receptor 2 and Mitogen- and Stress-activated Kinase 1 Are Effectors of Mycobacterium avium-induced Cyclooxygenase-2 Expression in Macrophages.
S. K. Pathak, A. Bhattacharyya, S. Pathak, C. Basak, D. Mandal, M. Kundu, and J. Basu (2004)
J. Biol. Chem. 279, 55127-55136
   Abstract »    Full Text »    PDF »
p38 MAP kinase-dependent regulation of endothelial cell permeability.
T. Borbiev, A. Birukova, F. Liu, S. Nurmukhambetova, W. T. Gerthoffer, J. G. N. Garcia, and A. D. Verin (2004)
Am J Physiol Lung Cell Mol Physiol 287, L911-L918
   Abstract »    Full Text »    PDF »
Long-term Potentiation of Wound-induced Exocytosis and Plasma Membrane Repair Is Dependant on cAMP-response Element-mediated Transcription via a Protein Kinase C- and p38 MAPK-dependent Pathway.
T. Togo (2004)
J. Biol. Chem. 279, 44996-45003
   Abstract »    Full Text »    PDF »
Protein Kinase R (PKR) Interacts with and Activates Mitogen-activated Protein Kinase Kinase 6 (MKK6) in Response to Double-stranded RNA Stimulation.
A. M. Silva, M. Whitmore, Z. Xu, Z. Jiang, X. Li, and B. R. G. Williams (2004)
J. Biol. Chem. 279, 37670-37676
   Abstract »    Full Text »    PDF »
Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38{alpha} Activation.
K. Ohkusu-Tsukada, N. Tominaga, H. Udono, and K. Yui (2004)
Mol. Cell. Biol. 24, 6957-6966
   Abstract »    Full Text »    PDF »
p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-{gamma} through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial Cells.
H. Huang, J. L. Rose, and D. G. Hoyt (2004)
Mol. Pharmacol. 66, 302-311
   Abstract »    Full Text »    PDF »
Ubiquitin-dependent Degradation of p73 Is Inhibited by PML.
F. Bernassola, P. Salomoni, A. Oberst, C. J. Di Como, M. Pagano, G. Melino, and P. P. Pandolfi (2004)
J. Exp. Med. 199, 1545-1557
   Abstract »    Full Text »    PDF »
Isoflurane Preconditioning Induces Neuroprotection against Ischemia via Activation of P38 Mitogen-Activated Protein Kinases.
S. Zheng and Z. Zuo (2004)
Mol. Pharmacol. 65, 1172-1180
   Abstract »    Full Text »
A Functional Interaction between the p75 Neurotrophin Receptor Interacting Factors, TRAF6 and NRIF.
J. J. Gentry, N. J. Rutkoski, T. L. Burke, and B. D. Carter (2004)
J. Biol. Chem. 279, 16646-16656
   Abstract »    Full Text »    PDF »
Induction of Apoptosis in Starfish Eggs Requires Spontaneous Inactivation of MAPK (Extracellular Signal-regulated Kinase) Followed by Activation of p38MAPK.
K. Sasaki and K. Chiba (2004)
Mol. Biol. Cell 15, 1387-1396
   Abstract »    Full Text »    PDF »
Activation of Discoidin Domain Receptor 1 Isoform b with Collagen Up-Regulates Chemokine Production in Human Macrophages: Role of p38 Mitogen-Activated Protein Kinase and NF-{kappa}B.
W. Matsuyama, L. Wang, W. L. Farrar, M. Faure, and T. Yoshimura (2004)
J. Immunol. 172, 2332-2340
   Abstract »    Full Text »    PDF »
p38 Mitogen-Activated Protein Kinase Activation and Cell Localization in Human Glomerulonephritis: Correlation with Renal Injury.
C. Stambe, D. J. Nikolic-Paterson, P. A. Hill, J. Dowling, and R. C. Atkins (2004)
J. Am. Soc. Nephrol. 15, 326-336
   Abstract »    Full Text »    PDF »
The Role of p38{alpha} Mitogen-Activated Protein Kinase Activation in Renal Fibrosis.
C. Stambe, R. C. Atkins, G. H. Tesch, T. Masaki, G. F. Schreiner, and D. J. Nikolic-Paterson (2004)
J. Am. Soc. Nephrol. 15, 370-379
   Abstract »    Full Text »    PDF »
p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes.
H. Kan, Z. Xie, and M. S. Finkel (2004)
Am J Physiol Cell Physiol 286, C1-C7
   Abstract »    Full Text »    PDF »
Feedback control of the protein kinase TAK1 by SAPK2a/p38{alpha}.
P. C. F. Cheung, D. G. Campbell, A. R. Nebreda, and P. Cohen (2003)
EMBO J. 22, 5793-5805
   Abstract »    Full Text »    PDF »

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