MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap

Abstract

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 carboxyltermini. 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.

Asymmetric Localization of Vangl2 and Fz3 Indicate Novel Mechanisms for Planar Cell Polarity in Mammals

“…A previous paper showed that MAGI-3 (membrane-associated guanylate cyclase with inverted orientation-3) could function as a scaffold protein for Fz4 and Vangl2 to regulate the c-Jun N-terminal protein kinase cascade. However, whereas the authors identified a direct interaction between MAGI-3 and Fz4 or Fz7, no interaction was demonstrated between MAGI-3 and Fz3 or Fz6 nor between Fz4 and Vangl2 (Yao et al, 2004).…”

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

“…A further question to address is, whether MAGI1 could itself be downregulated by Wnt signaling in CRC cells, thereby creating a self-sustaining loop much alike COX-2, which is both a Wnt-activating protein and a Wnt target gene (Araki et al, 2003;Buchanan and DuBois, 2006). Interestingly, MAGI3 was shown to bind to the Wnt receptors Frizzled-4 and Frizzled-7 (Yao et al, 2004), and to Ltap, a protein homologous to Stbm, which genetically interacts with frizzled to regulate Wnt signaling in Drosophila (Taylor et al, 1998;Wolff and Rubin, 1998). In epithelial cells, MAGI3 and Frizzled-4 form a complex that localizes at cell contact sites (Yao et al, 2004).…”

“…Interestingly, MAGI3 was shown to bind to the Wnt receptors Frizzled-4 and Frizzled-7 (Yao et al, 2004), and to Ltap, a protein homologous to Stbm, which genetically interacts with frizzled to regulate Wnt signaling in Drosophila (Taylor et al, 1998;Wolff and Rubin, 1998). In epithelial cells, MAGI3 and Frizzled-4 form a complex that localizes at cell contact sites (Yao et al, 2004). Taken together, these observations suggest that MAGI1 may be a physiological regulator of Wnt signaling.…”

Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2

“…Pro-IL-16 is an abundant protein constitutively expressed in human peripheral blood T cells that can induce cell growth arrest. MAGI-3 belongs to the same MAGUK family as hDlg and has been implicated in several cellular signaling pathways involved in cell survival as well as cell polarity (Wu et al, 2000;Adamsky et al, 2003;Wilson et al, 2003;Ohashi et al, 2004;Yao et al, 2004).…”