Journal
JOURNAL OF CELL SCIENCE
Volume 121, Issue 2, Pages 234-245Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.021964
Keywords
WNT; beta-catenin; JNK; Heterotrimeric g-proteins; frizzled; G alpha(o); dishevelled; planar cell polarity
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Funding
- NIDDK NIH HHS [DK30111] Funding Source: Medline
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In Drosophila, activation of Jun N-terminal Kinase (JNK) mediated by Frizzled and Dishevelled leads to signaling linked to planar cell polarity. A biochemical delineation of WNT-JNK planar cell polarity was sought in mammalian cells, making use of totipotent mouse F9 teratocarcinoma cells that respond to WNT3a via Frizzled-1. The canonical WNT-beta-catenin signaling pathway requires both G alpha(o) and G alpha(q) heterotrimeric G-proteins, whereas we show that WNT-JNK signaling requires only G alpha(o) protein. G alpha(o) propagates the signal downstream through all three Dishevelled isoforms, as determined by epistasis experiments using the Dishevelled antagonist Dapper1 (DACT1). Suppression of either Dishevelled-1 or Dishevelled-3, but not Dishevelled-2, abolishes WNT3a activation of JNK. Activation of the small GTPases RhoA, Rac1 and Cdc42 operates downstream of Dishevelled, linking to the MEKK 1/MEKK 4-dependent cascade, and on to JNK activation. Chemical inhibitors of JNK (SP600125), but not p38 (SB203580), block WNT3a activation of JNK, whereas both the inhibitors attenuate the WNT3a-beta-catenin pathway. These data reveal both common and unique signaling elements in WNT3a-sensitive pathways, highlighting crosstalk from WNT3a-JNK to WNT3a-beta-catenin signaling.
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