Biochemistry is an academic discipline to understand organisms as a system regulated by chemical reactions. By the middle of 1950’s, proteins, carbohydrate, and lipids in our body were isolated, and the mechanisms of the conversion between them and energy metabolisms were clarified. The biggest outcome was "the discovery of citric acid cycle and co-enzyme A and its importance for intermediary metabolism" by HA Krebs and FA Lipmann awarded the Nobel Prize in Physiology or Medicine in 1953. Interestingly, in the same year, JD Watson and FH Click proposed DNA double strand model. Owing to the development of technology in molecular biology, nucleic acids could be also handled by the late 1970’s. Figuring out the structure and function of four major organic compounds, including proteins, carbohydrates, lipids, and nucleic acids lead to the understanding of "life". Academic fields, such as biochemistry, biophysics, cell biology, and anatomy, which were mainly categorized by methodology, have been getting close to each other and they have also been integrated into life science research. Life science has been greatly progressed in the last two decades of the 20th century. The typical example of important outcomes was a human genome project. Most of studies were mainly done by a reductive approach to decompose cells into their components.
So far we purified numerous small GTP-binding proteins and their regulators and determined their nucleotide and amino acid sequences and their post translational modification, and clarified functions between the late 1980’s and the middle 1990’s. Furthermore, between the late 1990’s and the early 2000’s, we identified novel Wnt-related proteins and analyzed their physiological roles. The following results are our important contributions to the Wnt research field: 1) Axin forms a complex with β-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK-3β), and Dvl, and promotes the degradation of β-catenin by stimulating GSK-3β-dependent phosphorylation of β-catenin; 2) Sumoylation is involved in the stabilization of β-catenin and stimulation of T-cell factor (Tcf)-dependent transcription; 3) Wnt3a-dependent receptor internalization through a caveolin-mediated route and Wnt5a-dependent receptor internalization through a clathrin-mediated route activate the β-catenin-dependent and -independent pathways, respectively; 4) Abnormal expression of Wnt5a is associated aggressiveness of gastric and prostate cancers, and administration of anti-Wnt5a antibody suppresses metastatic ability of gastric cancer cells in vivo; 5) Wnt signal is involved in mitotic and cytokinetic progression by regulating the binding of spindle microtubules and kinetochores and recruiting ESCRT proteins to the stembody, respectively.
We believe that our outcomes based on biochemistry indeed contributed to the understanding of the molecular mechanisms in the regulation of signal transduction, growth, motility, and vesicle trafficking in mammalian cells. However, the "whole" is not a sum of "parts". It shows new and different aspects as results of the molecular interaction when they are reconstituted. In addition, in order to understand whole-body, the communications between cells and between organs have to be considered. Therefore, although it is still important to analyze "life" at molecular levels using our fine biochemical techniques, we are challenging new methodology, including whole-body/in vivo and organ experiments. Keeping biochemical methodologies and thought in mind, we innovate our research to clarify the relationship between the impairment of signaling and diseases.
We focus on Wnt signaling pathway that are essential for animal development, organ morphogenesis, and disease pathogenesis as well as Hedgehog, FGF, and TGF-β signaling pathways. Based on results from our previous studies, we will clarify the molecular mechanisms of Wnt signaling network in various cellular responses and understand the relationship between its failure and diseases. We are also planning different angles of experiments at whole-body/in vivo levels by the use of Wnt-related knockout mice.