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Masahide Takahashi MD, PhDProfessor, Department of Tumor Pathology, Nagoya University Graduate School of Medicine


Specialized field

Experimental pathology
Mechanisms of carcinogenesis and organogenesis by oncogenes and cancer-related genes

Career Summary

1983-1985
Research Fellow, (Dana-Farber Cancer Institute, Harvard Medical School)
1985-1990
Research Fellow, (Division of Oncological Pathology, Aichi Cancer Center Research Institute)
1990-1991
Research Associate (Department of Pathology, Nagoya University School of Medicine)
1990-1995
Assistant Professor (Department of Pathology, Nagoya University School of Medicine)
1995-1996
Associate Professor (Department of Pathology, Nagoya University School of Medicine)
1996-2000
Professor (Department of Pathology, Nagoya University School of Medicine)
2000-
Professor (Department of Pathology, Nagoya University Graduate School

Research Theme

Roles of cancer-related genes in oncogenesis and organogenesis

Research Summary

Scientific achievements: The RET proto-oncogene encodes a receptor tyrosine kinase, and its mutations are responsible for the developments of several human diseases including multiple endocrine neoplasia type 2 (MEN 2), Hirschsprung’s disease (HSCR), papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). After we identified the RET gene in 1988 (Oncogene, 1988), we have revealed many important molecular mechanisms which control the developments of these diseases (Mol. Cell. Biol. 1995;Cancer Res. 1997;Gastroenterology, 2001; Cytokine Growth Factor Rev, 2001, et al.). Our studies indicate that gain-of-function mutations of RET cause MEN 2, PTC and MTC, whereas loss-of-function mutations cause HSCR. To study RET functions in vivo, we introduced these mutations to mouse RET gene and generated disease model mice of HSCR and MTC (Cancer Res. 2000; Development 2006).

In collaboration with Rosenthal’s group in Genentic Inc., we reported that RET is activated by GDNF family of ligands and GFRa coreceptors are necessary for RET activation (Nature 1996, 1997). Analyses of RET knockout mice suggested the important functions of RET in the developments of the enteric nervous system, kidney and spermatogenesis. We examined detailed RET signaling (Cytokine Growth Factor Rev, 2001), and determined the roles of each signaling in the developments of the enteric nervous system, kidney and spermatogenesis by generating and analyzing a series of RET mutant mice (Mol. Cell Biol. 2004; Development 2006).

Akt signaling, which is strongly activated by tyrosine kinases including RET, has been known to regulate cancer invasion and metastasis. Recently, we identified a novel Akt substrate, designated Girdin (Dev. Cell 2005). Girdin is an actin-binding protein which is essential in the cell motility. We demonstrated that Girdin plays important roles in the cancer invasion and metastasis (Cancer Res. 2008) and in the postnatal angiogenesis (Nature Cell Biol. 2008). We also have several evidences that Girdin is essential for neural development in vivo (unpublished data).

Future plans: RET controls cell survival with GDNF stimulation. In contrast, several reports suggested that RET expression induced apoptosis in a ligand-independent manner. We are analyzing RET mutant mice which lack RET pro-apoptosis activity. Interestingly, mutant mice show abnormal neural development. We believe that this study provides a new aspect of RET in neural and cancer development. By gene expression profiling experiments with RET activation, we identified several potentially interesting genes which are highly expressed in human cancer tissues. Among these genes, we are focusing on CD109 which negatively controls TGFb signaling. We hope CD109 can be a good diagnostic cancer marker and a therapeutic target in patients.

As Girdin plays important roles in both neural and cancer development, Girdin is a good research target in the GCOE project. We already identified several interesting signal molecules which associate with Girdin. Together with Girdin deficient mice, we are making Girdin mutant mice and conditional-knockout mice. These mutant mice will be good tools for analyzing in vivo function of Girdin. Girdin, DAPLE and a novel gene make a gene family which shares the similarity in N-terminal half of each gene. DAPLE was reported as a Wnt signaling modifier and is expressed in neural cells and cancer tissues. As each Girdin family gene appears to have unique functions, examining three Girdin family genes together should give us interesting result.

Principal Research Achievement

  1. Kitamura T et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nature Cell Biol. 10: 329-337 (2008)
  2. Jiang P et al. An actin-binding protein Girdin regulates the motility of breast cancer cells. Cancer Res. 68: 1310-1318 (2008)
  3. Asai N et al. Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. Development 133: 4507-4516 (2006)
  4. Uchida M et al. Dok-4 regulates GDNF-dependent neurite outgrowth through downstream activation of Rap1 and mitogen-activated protein kinase. J. Cell Sci. 119: 3067-3077 (2006)
  5. Enomoto A et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell 9: 389-402 (2005)
  6. Morinaga T et al. GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region. Nucleic Acids Res. 33: 4191-4201 (2005)
  7. Jijiwa M et al. A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Mol. Cell. Biol. 24: 8026-8036 (2004)
  8. Hashimoto M et al. Expression of CD109 in human cancer. Oncogene 23: 3716-3720 (2004)
  9. Fukuda T et al. Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinase. J. Biol. Chem. 277: 19114-19121 (2002)
  10. Iwashita T et al. Functional analysis of RET with Hirschsprung’s mutations affecting its kinase domain. Gastroenterology 121: 24-33 (2001)
  11. Takahashi M et al. The GDNF/RET signaling pathway and human diseases. Cysokine & Growth Factor Reviews 12: 361-373 (2001)
  12. Kawai K et al. Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation. Cancer Res. 60: 5254-5260 (2000)
  13. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary carcinoma, and Hirschsprung’s disease phenotype. Cancer Res. 57: 2870-2872 (1997)
  14. Klein RD et al. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387: 717-721 (1997)
  15. Treanor JJS et al. Characterization of a multicomponent receptor for GDNF. Nature 382: 80-83 (1996)
  16. Asai N et al. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol. Cell. Biol. 15: 1613-1619 (1995)
  17. Iwamoto T et al. Aberrant melanogenesis and melanocytic tumor development in transgenic mice that carry a metallothionein/ret fusion gene. EMBO J. 10: 3167-3175 (1991)
  18. Takahashi M et al. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42: 581-588 (1985)

Award

Incitement Award of the Japanese Cancer Association (1990 ,The Japanese Cancer Association )
JSP Yong Investigator Award (1993, The Japanese Society of Pathology)
Japan Pathology Award (2001 ,The Japanese Society of Pathology)
Yomiuri-Tokai Medical Award (2006, The Yomiuri Shimbun)

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