Professor Misuzu Seo

Area and Subject Taught Molecular and Cell Biology, Cell Signaling
Research Theme(s) (1)Regulation of neuronal and vascular development
(2)Targeting growth factor-mediated cell signaling for cancer therapy
Academic Degrees Ph. D (Pharmaceutical Sciences)
Keywords for Research Field Cancer Molecular Target Therapy, Angiogenesis, Neurogenesis, VEGF, FGF
Office Phone Number 81-75-705-1488
e-mail

Research Overview

VEGF-A /NRP1 signaling induces GIPC1/Syx complexes,
resulting in RhoA activation to promote survival and
growth of human malignant skin cancer cells.

Solid tumor growth in animals and in man is accompanied by neovascularization called angiogenesis. New capillary growth is elicited by a diffusible factor such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) generated by malignant tumor cells. There is evidence that overexpression of VEGF and FGF correlate poor prognosis. We are investigating the molecular mechanisms whereby VEGF and FGF mediate tumor progression. Anti-VEGF antibodies (such as Avastin) have received much attention lately for their ability to block tumor angiogenesis and prolong the life of cancer patients. Neuropilins (NRP1 and NRP2) are receptors for the VEGF family of angiogenesis stimulators. Previously, it was shown that VEGFs act via VEGF receptor tyrosine kinases, but it now appears that VEGF activity is also modulated by NRPs, which have no kinase activity. We would like to clarify the downstream signaling of VEGF-A/NRP1 that may stimulate proliferation and metastasis of malignant tumor cells. Now we focus on developing new antitumor agents, which target the VEGF/NRPs and/or FGF mediated cell signaling in malignant tumor cells.
The second important project of our group is to investigate the molecular mechanisms of congenital disorders caused by neuronal impairment. FGF regulates the survival and motility of neural cells in vertebrates. Especially, loss of the function of FGF signaling in the central nervous system accounts for many hereditary and congenital disorders. We are actively studying the role of FGF receptor 1 (FGFR1) and downstream signaling cascades in Kallmann syndrome (KS). KS is defined by the combination of hypogonadotropic hypogonadism (HH) and anosmia/ hyposmia. Loss-of-function mutations in the KS gene KAL2/FGFR1 account for roughly 10% of KS cases, leading to the autosomal dominant form the diseases. The smell deficiency in KS is related to a defect in olfactory bulb development, and hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. Clinical spectrum in KAL2/FGFR1 mutation positive patients ranges widely from typical KS phenotype to apparently normal phenotype with fertility, including anosmina/ hyposmia only phenotype. Our contributions in these research fields are expected to lead to the development of regenerative therapies for neuronal disorder patients, which are currently the center of attention, as well as novel cancer treatments.

Notable Publications and Works in the Last Three Years

  1. Shyoko MatsushimaManami Kondo、Akio Shimizu、Hirotsugu Asano、Misuzu Seo:Anosmin-1 induced angiogenesis in chick embryonal olfactory bulb. The 89th Annual meeting of the Japan Biochemistry Society, Sendai、2016.9.24-27 (Poster presentation)
  2. Ayumi Yoshida, Akio Shimizu, Hirotsugu Asano, Michael Klagsbrun, Misuzu Seo. The cytoplasmic domain of NRP1 interacts with GIPC1 and Syx to induce tumor proliferation. Sakura Science Plan, Kyoto Sangyo University, Faculty of Life Sciences, 2016.2.20 Poster presentation.
  3. Yoshida A, Shimizu A, Asano H, Kadonosono T, Kondoh SK, Geretti E, Mammoto A, Klagsbrun M, Seo M., VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells. Biol Open(9):1063-76 (2015)
  4. Ueno N, Shimizu A, Kanai M, Iwaya Y, Ueda S, Nakayama J, Seo K M*. Enhanced expression of Fibroblast Growth Factor Receptor 3 IIIc promotes human esophageal carcinoma cell proliferation. J. Histochem. Cytochem. 64(1):7-17 (2016)
  5. *Yoshida A, Shimizu A, Ueno N, Asano H, Kadonosono T, Kondoh SK, Klagsbrun M, Seo M.,VEGF-A/Neuropilin signal activates RhoA and promotes cancer growth and metastasis. BMB2015 (Biochemistry and Molecular Biology), Kobe, 2015.12.1-4. *Best Young Scientist Awards at the Annual Meeting of the BMB2015, Japan.
  6. Matsushima S., Shimizu A., Kondoh M., Asano H., Seo M. Anosmin-1 activated the PLC-PKC signaling pathway to induce tube formation in endothelial cells. Ibid.
  7. Kida A., Yasuki, M., Tokumura, S., Shimizu A., Asano H., Ishi Y., Seo M. Axonal guidance molecules Anosmin-1 and Netrin1 partially co-localize in developing embryonic chick olfactory nervous system. Ibid.
  8. Asano H., Takeuch Y., Shimizu A., Sato N., Seo M. Anosmin-1 directly regulates Netrin-1-induced growth cone collapus. Ibid.
  9. Ueno N, Shimizu A, Kanai M, Iwaya Y, Ueda S, Nakayama J, Seo K M*. Enhanced expression of Fibroblast Growth Factor Receptor 3 IIIc promotes human esophageal cancer malignant progression. Ibid.
  10. Ayumi Yoshida*, Akio Shimizu, Tetsuya Kadonosono, Shinae Kondo、Misuzu Seo:The VEGF-A/NRP1 signaling promotes cancer cell proliferation and metastasis. The 19th annual meeting of the Japanese association for Molecular Target Therapy of Cancer. Matsuyama, 2015.6.10-12 (Workshop, Oral presentation)
  11. Asano H., Takeuchi Y., Shimizu A., Sato N., Seo M.:Kallmann syndrome responsible gene Anosmin-1 directly binds to Netrin-1. The 62st annual meeting of the Japanese Biochemical Society, Kinki Branch, Kusatsu, 2015.5.16 (Oral &Poster presentation)
  12. Matsushima S., Kondo M., Shimizu A., Asano H., Seo, M.:Analysis of Anosmin-1 signaling during blood vessel formation. Ibid. 2015.5.16 (Oral &Poster presentation)
  13. Kondo M., Shimizu A., Asano H., Seo M.:Neuronal guidance molecule Anosmin-1 has the effect of endothelial cell proliferation, migration, and tube formation. Ibid. 2015.5.16 (Oral &Poster presentation)
  14. Yoshida A., Shimizu A., Kadonosono T., Kondo S., Klagsbrun M., Seo M. Inhibition of VEGF-A/NRP1signaling prevents cancer proliferation and metasatasis. bid. 2015.5.16 (Oral &Poster presentation).
  15. Ayumi Yoshida, Akio Shimizu, Nobuhiro Ueno, Hirotsugu Asano, Misuzu Seo. The VEGF-A/NRP-1 signaling promotes cancer cell proliferation, metastasis, and tumor angiogenesis. Sakura Science Plan, Kyoto Sangyo University, Faculty of Life Sciences, 2015.2.21 Poster presentation
  16. Ayumi Yoshida, Akio Shimizu、Tetsuya Kadonosono, Shinae Kondo, Michael Klagsbrun, Misuzu Seo:Membrane-permeable peptides block VEGF-A signaling and inhibit Neuropilin-1 binding to the downstream molecules. The 18th annual meeting of the Japanese association for Molecular Target Therapy of Cancer. Sendai, 2014.6.27 (Workshop, Oral presentation)
  17. Manami Kondo, Akio Shimizu, Hirotsugu Asano, Misuzu Seo: Physiological effect of Anosmin-1 and analysis of Anosmin-1 receptor on Endothelial cells. The 61st annual meeting of the Japanese Biochemical Society, Kinki Branch, Kyoto Sangyo University, Kyoto, 2014.5.17(Oral &Poster presentation)
  18. Ayumi Yoshida*, Akio Shimizu, Tetsuya Kadonosono, Shinae Kondo, Michael Klagsbrun、Misuzu Seo:VEGF-A/NRP1 stimulates GIPC1/Syx complex formation to promote RhoA activation, leading to cancer proliferation and invasion. Ibid. *Best Poster Awards at the Annual Meeting of the Japanese Biochemical Society, Kinki Branch.
  19. Waraphan Toniti, Akio Shimizu, Misuzu Seo: The roles of estrogen on canine mammary gland tumors: Clinical diagnosis and treatment. Ibid. (Oral &Poster presentation)