Regulation of signaling pathway by frizzled family and its biological significance.

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Serpentine receptor, frizzled, plays important roles in several signaling including Wnt canonical pathway. We have identified three frizzled interacting proteins (fzip) as binding partners for C-terminal cytoplasmic domain of frizzled proteins.Fzip-1 was a novel gene and was named GOPC. GOPC had a role in the vesicle transport of frizzled from the Golgi apparatus to the plasma membrane. Gene targeting of GOPC resulted in the failure of spermatogenesis, revealing its critical role for the vesicle transport from the Golgi apparatus to acrosome.Fzip-2 turned out to be identical to MAGI-3, a scaffold protein of membrane proteins. MAGI-3 specifically bound to frizzled-4 and 7 among mammalian frizzled family members. MAGI-3 also interacted with Ltap, a mouse PCP protein, and they formed ternary complex, which in turn regulated the JNK signaling.Fzip-3 was localized at centrosome as well as mitotic spindle in mitotic cells. Homozygous null mutants were embryonic lethal, while homozygous mutants of hypomorphic allele resulted in neonatal death, indicating its dose-dependent roles in mouse embryogenesis. Fzip-3 depleted MEFs showed abnormal mitosis, which seemed to be the primary defects in mutant mouse. Finally, we have established conditional mice and these mice provide us the opportunity to investigate function of fzip-3 in adult mouse.