Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd.
Genetic studies have identified Drosophila Naked Cuticle (Nkd) as an antagonist of the canonical Wnt/beta-catenin signaling pathway, but its mechanism of action remains obscure [Zeng, W., Wharton, K. A., Jr., Mack, J. A., Wang, K., Gadbaw, M., et al. (2000) Nature (London) 403, 789--795]. Here we have cloned a cDNA encoding a mammalian homolog of Drosophila Nkd, mNkd, and demonstrated that mNkd interacts directly with Dishevelled. Dishevelled is an intracellular mediator of both the canonical Wnt pathway and planar cell polarity (PCP) pathway. Activation of the c-Jun-N-terminal kinase has been implicated in the PCP pathway. We showed that mNkd acts in a cell-autonomous manner not only to inhibit the canonical Wnt pathway but also to stimulate c-Jun-N-terminal kinase activity. Expression of mNkd disrupted convergent extension in Xenopus, consistent with a role for mNkd in the PCP pathway. These data suggest that mNkd may act as a switch to direct Dishevelled activity toward the PCP pathway, and away from the canonical Wnt pathway.
Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA
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D
Yan
J B
JB
Wallingford
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TQ
Sun
A M
AM
Nelson
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Sakanaka
C
C
Reinhard
R M
RM
Harland
W J
WJ
Fantl
L T
LT
Williams
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D004789:Enzyme Activation; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; C424446:Nkd1 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C000606588:dsh protein, Drosophila; C405336:nkd protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases