Dishevelled Proteins Lead to Two Signaling Pathways

doi:10.1074/jbc.274.1.129

Dishevelled Proteins Lead to Two Signaling Pathways

REGULATION OF LEF-1 AND c-Jun N-TERMINAL KINASE IN MAMMALIAN CELLS*

From the ^‡Department of Pharmacology and Physiology and Department of Oncology, University of Rochester, Rochester, New York 14642-8711, ^§Shanghai Institute of Biochemistry, Chinese Academy of Science, Shanghai, People’s Republic of China,^‖Harvard University, Cambridge, Massachusetts 02163, and ^**Department of Obstetrics and Gynecology, University of Maryland, Baltimore, Maryland 21250

Abstract

Dishevelled (Dsh/Dvl) proteins are known to mediate Wnt signaling by up-regulating β-catenin levels and stimulating T cell factor (TCF)/LEF-1-dependent transcription. We have identified a new Dvl-mediated signaling pathway in that mouse Dvl proteins, when expressed in COS-7 cells, stimulate c-Jun-dependent transcription activity and the kinase activity of the c-Jun N-terminal kinase (JNK). The DEP domain of Dvl1 is essential for JNK activation. By contrast, all three conserved domains of Dvl, including DIX, PDZ, and DEP, are required for up-regulation of β-catenin and for stimulation of LEF-1-mediated transcription in mammalian cells. Thus, Dvl can lead to two different signaling pathways. Furthermore, the small G proteins of Cdc42 or Rac1, which are involved in JNK activation by many stimuli, do not appear to play a major role in Dvl-mediated JNK activation, because the dominant negative mutants of Cdc42 and Rac1 could not inhibit Dvl-induced JNK activation. This suggests that Dvl may activate JNK via novel pathways.

Footnotes

↵* This work is supported by National Institutes of Health Grants GM53162 and GM54167 and a grant from the National Heart Association (to D. W.) and by National Institutes of Health Grant CA63929 (to D. J. S.).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.
↵¶ First two authors contributed equally.
↵‡ To whom correspondence should be addressed. Tel.: 716-275-2029; Fax: 716-244-9283.
Abbreviations:

GSK

glycogen synthase kinase

APC

adenomatous polyposis coli

Arm

armadillo

Dsh/Dvl

Dishevelled

Fz

Frizzled

GFP

green fluorescence protein

JNK

c-Jun N-terminal kinase

LacZ

β-galactosidase

Pan

pangolin/DTcf

SRE

serum response element

SRF

serum response factor

Wg

wingless

Zw-3

zeste-white3: HA, hemagglutinin

EGF

epidermal growth factor.
- Received April 27, 1998.
- Revision received October 8, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.