title: G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA. kamesh@pharm.stonybrook.edu
authors.forename: Rama Kamesh
authors.initials: RK
authors.lastname: Bikkavilli
authors.forename: Michael E
authors.initials: ME
authors.lastname: Feigin
authors.forename: Craig C
authors.initials: CC
authors.lastname: Malbon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; C000606585:Dvl3 protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051155:Wnt1 Protein; D051176:beta Catenin; C000606588:dsh protein, Drosophila; D048728:MAP Kinase Kinase Kinase 1; D048768:MAP Kinase Kinase Kinase 4; C482576:MAP3K1 protein, human; C482779:MAP3K4 protein, human; D048670:MAP Kinase Kinase 4; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020742:rhoA GTP-Binding Protein