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

• Project/Area Number: 15570168
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: YAO Ryoji Japanese Foundation for Cancer Research, Cell Biology, Associate Member, 癌研究所・細胞生物部, 主任研究員 (80291095)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,700,000 (Direct Cost: ¥3,700,000); Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2003: ¥3,100,000 (Direct Cost: ¥3,100,000)
• Keywords: frizzled / Wnt / GOPC / MAGI-3 / Knockout mouse / wnt / knockout mouse / Frizzled / Ltap / JNK

Research Abstract

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.

Research Products

• [Journal Article] The coiled tail of the round-headed spermatozoa appears during epididymal passage in GOPC-deficient mice. (2004)
  • Author(s): Suzuki-Toyama, F.Ito, C.Toyama, Y.Maekawa, M.Yao, R.Noda, T.Toshimori, K.
  • Journal Title: Arch. Histol. Cytol. 67(4) Pages: 361-371
  • NAID: 10014259591
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Failure to assemble the peri-nuclear structures in GOPC deficient spermaticds as found in round-headed spermatozoa. (2004)
  • Author(s): Ito, C.Suzuki-Toyoda, F.Maekawa, M.Toyama, Y.Yao, R.Noda, T.Toshimori, K.
  • Journal Title: Arch. Histol. Cytol. 67(4) Pages: 349-360
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap. (2004)
  • Author(s): Yao, R.Natsume, Y.Noda, T.
  • Journal Title: Oncogene 23(36) Pages: 6023-6030
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. (2004)
  • Author(s): Nakamura, T.Yao, R.Ogawa, T.Suzuki, T.Ito, T.Tsunekawa, T.Inoue, K.Ajima, R.Miyasaka, T.Yoshida, Y.Ogura, A.Toshimori, K.Noze, T.Yamamoto, T.Noda, T.
  • Journal Title: Nat. Genet. 36(5) Pages: 528-533
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The coiled tail of the round-headed spermatozoa appears during epididymal passage in GOPC-deficient mice (2004)
  • Author(s): Suzuki-Toyota, F., Ito, C., Toyama, Y., Maekawa, M., Yao, R., Noda, T., Toshimori, K.
  • Journal Title: Arch.Histol.Cytol. 67(4) Pages: 361-371
  • NAID: 10014259591
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Failure to assemble the peri-nuclear structures in GOPC deficient spermaticds as found in round-headed spermatozoa (2004)
  • Author(s): Ito, C., Suzuki-Toyoda, F., Maekawa, M., Toyama, Y., Yao, R., Noda, T., Toshimori, K.
  • Journal Title: Arch.Histol.Cytol. 67(4) Pages: 349-360
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap (2004)
  • Author(s): Yao, R., Natsume, Y., Noda, T.
  • Journal Title: Oncogene 23(36) Pages: 6023-6030
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta (2004)
  • Author(s): Nakamura, T., Yao, R., Ogawa, T., Suzuki, T., Ito, T., Tsunekawa, T., Inoue, K., Ajima, R., Miyasaka, T., Yoshida, Y., Ogura, A., Toshimori, K., Noce, T., Yamamoto, T., Noda, T.
  • Journal Title: Nat.Genet. 36(5) Pages: 528-533
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The coiled tail of the round-headed spermatozoa appears during epididymal passage in GOPC-deficient mice. (2004)
  • Author(s): Suzuki-Toyota, F., Ito, C., Toyama, Y., Maekawa, M., Yao, R., Noda, T., Toshimori, K.
  • Journal Title: Arch.Histol.Cytol. 67(4) Pages: 361-371
  • NAID: 10014259591
• [Journal Article] Failure to assemble the peri-nuclear structures in GOPC deficient spermaticds as found in round-headed spermatozoa. (2004)
  • Author(s): Ita, C.Suzuki-Toyoda, F., Maekawa, M., Toyama, Y., Yao, R., Noda, T., Toshimori M.
  • Journal Title: Arch.Histol.Cytol. 67(4) Pages: 349-360
• [Journal Article] MAGI-3 is involved in the regulation of JNK signaling pathway as a scaffold protein for frizzled and Ltap. (2004)
  • Author(s): Yao, R., Natsume, Y., Noda, T.
  • Journal Title: Oncogene 23(36) Pages: 6023-6030
• [Journal Article] Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. (2004)
  • Author(s): Nakamura, T., Yao R., Ogawa, T., Suzuki, T., Ito, T., Tsunekawa, T., Inoue, K., Ajima, R., Miyasaka, T., Yoshida, Y., Ogura, A., Toshimori, K., Noce, T., Yamamoto, T., Noda, T.
  • Journal Title: Nat.Genet. 36(5) Pages: 528-533
• [Journal Article] Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor β-induced repression of c-myc. (2003)
  • Author(s): Sasaki, T.Suzuki, H.Yagi, K.Furuhashi, M.Yao, R.Susa, S.Noda, T.Arai, Y.Miyazono, K.Kato, M.
  • Journal Title: Cancer Res. 63(4) Pages: 801-806
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor β-induced repression of c-myc (2003)
  • Author(s): Sasaki, T., Suzuki, H., Yagi, K., Furuhashi, M., Yao, R., Susa, S., Noda, T., Arai, Y., Miyazono, K., Kato, M.
  • Journal Title: Cancer Res. 63(4) Pages: 801-806
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] T.Nakamura, R.Yao, et al.(total 15, 2nd): "Oligo-astheno-teratozoospermia in mice lacking CCR4-associated factor 1, a novel regulator of RXRβ."Nature Genetics. in press. (2004)
• [Publications] T.Sasaki, R.Yao, et al.(total 10, 5th): "Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc."Cancer Res.. 63(4). 801-806 (2003)