Professor Misuzu Seo

Area and Subject Taught Molecular and Cell Biology, Cell Signaling
Research Theme(s) Regulation of Cell Proliferation and Differentiation by Growth Factors and Cell Signaling
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. Fukami M, Iso M, Sato N, Igarashi M, Seo M, Kazukawa I, Kinoshita E, Dateki S, Ogata T. Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. (2013.5) Endocr J. : in press, PMID: 23657145
  2. Ayumi Yoshida, Akio Shimizu, Misuzu Seo*. VEGF-A/NRP1 signaling induces GIPC1/Syx complexes, resulting in RhoA activation to promote survival and growth of human malignant skin cancer cells. (2013.4) Vascular Biology Program Seminar, Harvard Medical School, Children’s Hospital Boston, Boston, U. S. A., *invited lecture
  3. Ayumi Yoshida, Akio Shimizu, Michael Klagsbrun, Misuzu Seo:VEGF-A/NRP1 signaling induces proliferation of human malignant cancer cells. (2013.5) (Oral & poster presentation)The 60th annual meeting of the Japanese Biochemical Society, Kinki Branchi, Osaka, Suita-shi.
  4. Yoshito Takeuchi, Akio Shimizu, Sayaka Okamoto, Misuzu Seo:Study of the molecular mechanisms in which Anosmin-1 inhibits the collapse of growth cone by RGMa. (2013,5) (Oral & poster presentation)The 60th annual meeting of the Japanese Biochemical Society, Kinki Branchi, Osaka, Suita-shi.
  5. Ayumi Yoshida, Akio Shimizu, Misuzu Seo:VEGF-A/Neuropilin-1 signaling promotes growth of human malignant skin cancer cells by the autocrine mexhanism. (2013,6) (Oral & poster presentation)The 17th annual meeting of the Japanese association for Molecular Target Therapy of Cancer. Kyoto-shi.
  6. Takeuchi Y, Kitagawa H, Yoshida A, Asano H, Shimizu A, Okamoto S, Seo M. Anosmin-1 inhibits RGMa and Netrin-1 signaling through Neogenin to prevent the growth cone collapse. (2013. 12) (Poster presentation) The 36th Annual Meeting of the Molecular Biology Society of Japan, Kobe-shi.