MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap.
A seven-transmembrane protein, frizzled, has been implicated in a planar cell polarity (PCP) pathway as well as the canonical Wnt signaling pathway. Although both pathways require a cytoplasmic protein, dishevelled, the molecular mechanism by which frizzled regulates intracellular signaling remains to be elucidated. In the mouse, nine frizzled family members have been identified and six of them contain a PDZ-binding motif at their carboxyl-termini. In this study, we show that a multi-PDZ containing protein, MAGI-3, specifically binds to frizzled-4 and -7. Furthermore, we also demonstrate that MAGI-3 interacts with Ltap, a mouse homolog of the Drosophila PCP protein, stbm, and that these three molecules can form a ternary complex. In epithelial cells, MAGI-3, frizzled-4, and Ltap colocalized at cell contact sites, indicating that these molecules form a physiologically significant complex. Finally, we found that MAGI-3 strongly activated JNK in conjunction with frizzled-4 and Ltap, and that this activation required the small GTPase, Rac. These results indicate that MAGI-3 functions as a scaffold protein for frizzled-4 and Ltap and regulates the JNK signaling cascade.
Yao
Ryoji
R
Department of Cell Biology, The JFCR-Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Natsume
Yasuko
Y
Noda
Tetsuo
T
D000818:Animals; D002460:Cell Line; D051157:Frizzled Receptors; D051528:Guanylate Kinases; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020798:Two-Hybrid System Techniques
C402930:FZD4 protein, human; C115810:FZD7 protein, human; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C431577:Ltap protein, mouse; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D048031:JNK Mitogen-Activated Protein Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases