HOME > Members > GCOE Organizing Members > Masahide Takahashi MD, PhD

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

Research Fellow, (Dana-Farber Cancer Institute, Harvard Medical School)
Research Fellow, (Division of Oncological Pathology, Aichi Cancer Center Research Institute)
Research Associate (Department of Pathology, Nagoya University School of Medicine)
Assistant Professor (Department of Pathology, Nagoya University School of Medicine)
Associate Professor (Department of Pathology, Nagoya University School of Medicine)
Professor (Department of Pathology, Nagoya University School of Medicine)
Professor (Department of Pathology, Nagoya University Graduate School

Research Theme

Roles of cancer-related genes in oncogenesis and organogenesis

Research Summary

Background and Objectives
Cell migration is a fundamental aspect of a multitude of physiological and pathological processes, including embryonic development, inflammation, wound healing, angiogenesis, and cancer progression. Previously, we identified a novel protein termed Girdin (girders of actin filaments), a component of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which plays a crucial role in the regulation of angiogenesis and neurogenesis that occur in the postnatal period and adult life. In the present study, we elucidated the molecular mechanisms of Girdin-mediated cell migration by identifying novel Girdin-interacting proteins. Also, we studied the role of Daple (Dishevelled-associating protein with a highly frequency of leucine residues), a member of the Girdin family of proteins, in cell migration regulated by the Wnt signaling pathway.

Results and Achievement
We recently showed that Girdin-deficient mice exhibit a severe defect in the migration of neuroblasts born in the subventricular zone (SVZ) toward the olfactory bulb (OB) through the rostral migratory stream (RMS). Our immunohistochemical analysis revealed that the polarization of SVZ neuroblasts in Girdin-deficient mice was significantly disrupted, which suggests the involvement of Girdin in the establishment and/or maintenance of cell polarity. We found that Girdin directly interacts with Par-3, a component of the Par protein complex that has an established role in determining cell polarity. Our biochemical study showed that the CT domain of Girdin interacts with the middle part of the 4N domain (4N/2) of Par-3. Disruption of Girdin/Par-3 interaction as well as RNAi-mediated depletion of Girdin abrogated cell polarization in migrating cells as assessed by the location of the centrosomes. Further biochemical analysis suggests that Girdin is present in the Par protein complex that includes Par-3, Par-6, and atypical protein kinase C (aPKC). These data may provide a specific mechanism by which Girdin regulates cell movement through the establishment of cell polarity. Considering that Girdin is aberrantly expressed in certain types of cancer, including breast and colon cancers, and glioblastomas, a future experimental challenge is to verify how Girdin, its transcriptional regulation, and its interaction with Par-3 are involved in the determination of cell polarization and tissue architecture in human malignancies.
We next explored the function of Daple in cell migration that depends on the Wnt signaling pathway. Previous studies have shown that Daple interacts with Dishevelled (Dvl), the common mediator of canonical and non-canonical Wnt signaling pathways, which are important for development, tissue maintenance, and cancer progression. In the non-canonical Wnt signaling pathway, the Rho family of small GTPases acting downstream of Dvl plays essential roles in cell migration. The mechanisms by which the non-canonical Wnt signaling pathway regulates Rac activation remain unknown. In the present study, we showed that Daple/Dvl interaction regulates Wnt5a-mediated activation of Rac and formation of lamellipodia. In Wnt5a-stimulated cells, Daple stabilizes the interaction of Dvl with aPKC, leading to the increase of aPKC activity and Rac activation. Accordingly, in Daple-deficient mice that we generated, the migration of fibroblasts and epithelial cells was significantly impaired during wound healing in vivo. These findings indicate that Daple interacts with Dvl to direct the Dvl/aPKC protein complex to activate Rac, which in turn mediates the non-canonical Wnt signaling pathway required for cell migration.

Principal Research Achievement

  1. Natsume A, Kato T, Kinjo S, Enomoto A, Toda H, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T: Girdin maintains the stemness of glioblastoma stem cells. Oncogene, in press (2012)
  2. Kee HJ, Kim JR, Joung H, Choe N, Lee SE, Eom GH, Kim JC, Geyer SH, Jijiwa M, Kato T, Kawai K, Weninger WJ, Seo SB, Nam KI, Jeong MH, Takahashi M, Kook H: Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1. Cell Death Differ, 19, 121-131 (2012)
  3. Ohgami N, Ida-Eto M, Sakashita N, Sone M, Nakashima T, Tabuchi K, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi M, Kato M: Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice. Neurobiol Aging, 33, 626 e625-634 (2012)
  4. Asano E, Maeda M, Hasegawa H, Ito S, Hyodo T, Yuan H, Takahashi M, Hamaguchi M, Senga T: Role of palladin phosphorylation by extracellular signal-regulated kinase in cell migration. PLoS One, 6, e29338 (2011)
  5. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K: Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet, 20, 4666-4683 (2011)
  6. Motegi Y, Katayama K, Sakurai F, Kato T, Yamaguchi T, Matsui H, Takahashi M, Kawabata K, Mizuguchi H: An effective gene-knockdown using multiple shRNA-expressing adenovirus vectors. J Control Release, 153, 149-153 (2011)
  7. Wang Y, Kaneko N, Asai N, Enomoto A, Isotani-Sakakibara M, Kato T, Asai M, Murakumo Y, Ota H, Hikita T, Namba T, Kuroda K, Kaibuchi K, Ming GL, Song H, Sawamoto K, Takahashi M: Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain. J Neurosci, 31, 8109-8122 (2011)
  8. Miyake H, Maeda K, Asai N, Shibata R, Ichimiya H, Isotani-Sakakibara M, Yamamura Y, Kato K, Enomoto A, Takahashi M, Murohara, T: The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury. Circ Res, 108, 1170-1179 (2011)
  9. Saito S, Murakumo Y, Tsuzuki T, Dambara A, Kato T, Enomoto A, Asai N, Maruyama S, Matsuo S, Takahashi M: Analysis of GDNF-inducible zinc finger protein 1 expression in human diseased kidney. Human Pathol, 42, 848-858 (2011)
  10. Matsushita E, Asai N, Enomoto A, Kawamoto Y, Kato T, Mii S., Maeda K, Shibata R, Hattori S, Hagikura M, Takahashi K, Sokabe M, Murakumo Y, Murohara T, Takahashi M: Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cell. Mol Biol Cell, 22, 736-747 (2011)
  11. Miyamoto R, Jijiwa M, Asai M, Kawai K, Ishida-Takagishi M, Mii S, Asai N, Enomoto A, Murakumo Y, Yoshimura A, Takahashi, M: Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice. Dev Biol, 349, 160-168 (2011)
  12. Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S, Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai K, Nakamura S, Gotoh M, Takahashi M: Correlation of pathological grade and tumor stage of urothelial carcinoma with CD109 expression. Pathol Int, 60, 735-743 (2010)
  13. Ohgami N, Ida-Eto M, Shimotake T, Sakashita N, Sone M, Nakashima T, Tabuchi K, Hoshino T, Shimada A, Tsuzuki T, Yamamoto M, Sobue G, Jijiwa M, Asai N, Hara A, Takahashi, M, Kato M: c-Ret-mediated hearing loss in mice with Hirschsprung disease. Proc Natl Acad Sci USA, 107, 13051-13056 (2010)
  14. Yamaguchi M, Suyari O, Nagai R, Takahashi M: dGirdin a new player of Akt /PKB signaling in Drosophila Melanogaster. Front Biosci, 15, 1164-1171 (2010)
  15. Weng L, Enomoto A, Ishida-Takagishi M, Asai N, Takahashi M: Girding for migratory cues: Role of the Akt substrate Girdin in cancer progression and angiogenesis. Cancer Sci, 101, 836-842 (2010)
  16. Kurotsuchi A, Murakumo Y, Jijiwa M, Kurokawa K, Itoh Y, Kodama Y, Kato T, Enomoto A, Asai N, Terasaki H, Takahashi M: Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells. Cancer Sci, 101, 1147-1155 (2010)
  17. Kato M, Takeda K, Hossain K, Thang ND, Kaneko Y, Kumasaka M, Yamanoshita O, Uemura N, Takahashi M, Ohgami N, Kawamoto Y: A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation. J Cell Biochem, 110, 399-407 (2010)
  18. Hagiwara S, Murakumo Y, Mii S, Shigetomi T, Yamamoto N, Furue H, Ueda M, Takahashi M: Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene, 29, 2181-2191 (2010)
  19. Ohshima Y, Yajima I, Kumasaka MY, Yanagishita T, Watanabe D, Takahashi M, Inoue Y, Ihn H, Matsumoto Y, Kato M: CD109 expression levels in malignant melanoma. J Dermatol Sci, 57, 140-142 (2010)
  20. Kumasaka MY, Yajima I, Hossain K, Iida M, Tsuzuki T, Ohno T, Takahashi M, Yanagisawa M, Kato M: A novel mouse model for de novo Melanoma. Cancer Res, 70, 24-29 (2010)
  21. Hagiwara S et al., Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene, in press (2010)
  22. Lu B, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, Arber S, Hassell J, MacNeil L, Hoshi M, Jain S, Asai N, Takahashi M, Schmidt-Ott K, Barasch J, D’Agati V. Costantini F. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature Genet, 41, 1295-1302 (2009)
  23. Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of Disrupted-in-Schizophrenia 1-interacting protein Girdin in postnatal development of the dentate gyrus. Neuron, 63, 774-787 (2009)
  24. Puseenam A, Yoshioka Y, Nagai R, Hashimoto R, Suyari O, Itoh M, Enomoto A, Takahashi M, Yamaguchi M. A novel Drosophila Girdin-like protein is involved in Akt pathway control of cell size. Exp Cell Res, 315, 3370-3380 (2009)
  25. Jiang P, Enomoto A, Takahashi M. Cell biology of the movement of breast cancer cells: intracellular signaling and the actin cytoskeleton. Cancer Lett, 284, 122-130 (2009)
  26. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht JD, Asai N, Takahashi M, Ohgami N, Kato M, Mendelsohn C, Costantini, F. Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell, 17, 199-209 (2009)
  27. Kato T, Shimono Y, Hasegawa M, Jijiwa M, Enomoto A, Asai N, Murakumo Y, Takahashi M. Characterization of the HDAC1 complex that regulates the sensitivity of cancer cells to oxidative stress. Cancer Res, 69, 3597-3604 (2009)
  28. Hasegawa T, Enomoto A, Kato T, Kawai K, Miyamoto R, Jijiwa M, Ichiahara M, Ishida M, Asai N, Murakumo Y, Ohara K, Niwa Y, Goto H, Takahashi M. Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. Oncogene, 27, 5684-5695 (2008)
  29. Jijiwa M, Kawai K, Fukihara J, Nakamura A, Hasegawa M, Suzuki C, Sato T, Enomoto A, Asai N, Murakumo Y, Takahashi M. GDNF-mediated Signaling via RET Tyrosine 1062 is Essential for Maintenance of Spermatogonial Stem Cells. Genes Cells, 13, 365-374 (2008)
  30. Kitamura T et al. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nature Cell Biol. 10: 329-337 (2008)
  31. Jiang P et al. An actin-binding protein Girdin regulates the motility of breast cancer cells. Cancer Res. 68: 1310-1318 (2008)
  32. 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)
  33. 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)
  34. Enomoto A et al. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell 9: 389-402 (2005)
  35. 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)
  36. 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)
  37. Hashimoto M et al. Expression of CD109 in human cancer. Oncogene 23: 3716-3720 (2004)
  38. 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)
  39. Iwashita T et al. Functional analysis of RET with Hirschsprung’s mutations affecting its kinase domain. Gastroenterology 121: 24-33 (2001)
  40. Takahashi M et al. The GDNF/RET signaling pathway and human diseases. Cysokine & Growth Factor Reviews 12: 361-373 (2001)
  41. 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)
  42. 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)
  43. Klein RD et al. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387: 717-721 (1997)
  44. Treanor JJS et al. Characterization of a multicomponent receptor for GDNF. Nature 382: 80-83 (1996)
  45. 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)
  46. 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)
  47. Takahashi M et al. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42: 581-588 (1985)


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)