Axin Forms a Complex with MEKK1 and Activates c-Jun NH2-terminal Kinase/Stress-activated Protein Kinase through Domains Distinct from Wnt Signaling*
- From the Regulatory Biology Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609, Republic of Singapore and the§Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
Abstract
Axin negatively regulates the Wnt pathway during axis formation and plays a central role in cell growth control and tumorigenesis. We found that Axin also serves as a scaffold protein for mitogen-activated protein kinase activation and further determined the structural requirement for this activation. Overexpression of Axin in 293T cells leads to differential activation of mitogen-activated protein kinases, with robust induction for c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase, moderate induction for p38, and negligible induction for extracellular signal-regulated kinase. Axin forms a complex with MEKK1 through a novel domain that we term MEKK1-interacting domain. MKK4 and MKK7, which act downstream of MEKK1, are also involved in Axin-mediated JNK activation. Domains essential in Wnt signaling, i.e.binding sites for adenomatous polyposis coli, glycogen synthase kinase-3β, and β-catenin, are not required for JNK activation, suggesting distinct domain utilization between the Wnt pathway and JNK signal transduction. Dimerization/oligomerization of Axin through its C terminus is required for JNK activation, although MEKK1 is capable of binding C terminus-deleted monomeric Axin. Furthermore, Axin without the MEKK1-interacting domain has a dominant-negative effect on JNK activation by wild-type Axin. Our results suggest that Axin, in addition to its function in the Wnt pathway, may play a dual role in cells through its activation of JNK/stress-activated protein kinase signaling cascade.
Footnotes
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↵* This research was funded by the National Science and Technology Board of Singapore (to S.-C. L.) and by National Institutes of Health Grants GM51417 and AI41637 (to J. H.).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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↵‡ These authors contributed equally to this work.
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↵¶ To whom correspondence should be addressed. Tel.: 65-779-4560; Fax: 65-779-1117; E-mail: mcblinsc@imcb.nus.edu.sg.
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↵2 C. Chen, and S.-C. Lin, unpublished observations.
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↵3 Y. Zhang, S. Y. Neo, L. P. Yaw, and S.-C. Lin, manuscript in preparation.
- Abbreviations:
- APC
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adenomatous polyposis coli
- DIX
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Dishevelled homologous
- ERK
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extracellular signal-regulated kinase
- GSK-3β
-
glycogen synthase kinase-3β
- JNK
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c-Jun NH2-terminal kinase
- SAPK
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stress-activated protein kinase
- MAPK
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mitogen-activated protein kinase
- RGS
-
regulator of G protein signaling
- HA
-
hemagglutinin
- GST
-
glutathioneS-transferase
- aa
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amino acid(s)
- MID
-
MEKK1-interacting domain
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- Received August 5, 1999.
- Revision received September 28, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
