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SEKIGUCHI Biomatrix Signaling
Research Director: Kiyotoshi Sekiguchi
(Institute for Protein Research, Osaka University)
Research Term 2000-2005
Outline of Research Results

 Perhaps the most powerful and long-lasting image in biology is that the basic component of living organisms is the cell. The region between cells has generally been ignored as only a vast scaffold surrounded by an inert fluid that is simply needed to hold cells together into a structural whole. This outdated view is rapidly changing.

 The reason for this change is that along with ever-better observational technology and experimental techniques, the intercellular region - the extracellular matrix - has been shown to be not only far more complex than earlier imagined, but that many chemical processes occur there that allow the cells to live and grow, undergo differentiation, find their proper location, and even undergo appatosis. Cells cannot exist without this region. In a way, the intercellular region provides a holistic whole to any multicellular organism.

 As a very simple view, organisms are made up of two types of basic structures: one is the epithelium, a sheet of cells that covers the outer surface of any organism as well as that of internal organs; the other is connective tissues that underlie the epithelium and provide the mechanical strength of tissues/organs. These two structures are separated by a special type of extracellular matrix, called the basement membrane. The basement membrane is thus the direct environment or supporting structure for epithelial cells and is considered to play a critical role in the regulation of the growth and differentiation of epithelial cells.

 The importance of the basement membrane has been highlighted by recent progress in genome analyses of worms (C. elegans) and flies (Drosophila). Among the many kinds of molecules that form the extracellular matrices, those of the basement membrane are consistently present in these organisms, although those forming connective tissues are not. Thus, the basement membrane appears to be the most primordial form of extracellular matrix prerequisite for the evolution of multicellular organisms.

 Epithelial cells adhere to the basement membrane through receptors on the cell surface, which bind to the constituents of the basement membrane, particularly those of the laminin family of cell-adhesive proteins. The main receptors for the basement membrane proteins are integrins, a family of more than twenty members with distinct binding specificities. One binds to certain types of laminins and another binds to other laminins or type IV collagen, a basement membrane-specific collagen. All types of epithelial cells need to adhere to the basement membrane to survive, grow, and maintain their differentiated phenotypes.

 The basement membrane is not only a substrate for the epithelial cells to adhere to, but also a reservoir for hormones and growth factors, many of which are needed to be assembled in the extracellular matrix to act on target cells. Unlike these soluble factors that interact with cells only transiently, the basement membrane is always in contact with cells and continuously sending signals through the receptors. The cell nucleus always needs some signals or clues about how to activate, and which genes to activate under different situations. Both signals from the basement membrane, and soluble factors need to merge to be effective; if either signal or receptor is denied, the cell starts to die.

Outline of Research

 The basic concept of the Sekiguchi Biomatrix Signals project is the importance of the extracellular matrix, which in a broad sense includes connective tissues and the basement membranes, as well as the regulation of cell growth, cell differentiation, and appatosis. This project is divided into three main research areas:

 One area concerns how the matrix transduces signals. Thus, an effort is being made to understand the interactions of the extracellular molecules, particularly the laminins with the integrins. Also of interest is how integrins signal within a cell after having bonded with the basement membrane.

 Another area is how the basement membranes self-assemble beneath the epithelial cells. The major components, like laminins, are synthesized by epithelial cells and connective tissue cells. Both are necessary. An effort is being made to determine which parts of molecules are critical for the assembly, and how the basement membrane regulates or stabilizes differentiation while maintaining its specific phenotype. This also involves understanding the particular laminins in each specific tissue.

 The third area is designed to integrate the first and second areas with the aim to make an artificial basement membrane. This is not just to be a simple reconstituted membrane, but a more "intelligent" membrane incorporating growth factors. Efforts are also being made to stimulate the regenerating abilities in lower and possibly higher organisms, and eventually, maybe producing organs.



Research Director
Kiyotoshi Sekiguchi
(Institute for Protein Research, Osaka University)
Research Groups
Matrix Signaling
Group Leader:
 Daiji Kiyozumi
 Daiji Kiyozumi
 Aki Osada
Research assistant:
 Nagisa Sugimoto

Matrix Genomics
Group Leader:
 Yoshitaka Hayashi
 Hironobu Fujiwara
Research assistant:
 Noriko Sanzen
 Tomomi Emoto
 Charles N. Weber

Matrix Engineering
Group Leader:
 Ri-ichiroh Manabe
 Tomohiko Fukuda
 Ko Tsutsui
Research assistant:
 Itsuko Nakano
 Mina Kimura
 Yasuko Oguri
 Keiko Shimamoto
 Chisei Shimono
Research Advisor
Senior Research Advisor

Project Office
Annex to Aichi Medical University 21 Yazako-karimata, Nagakute Aichi 480-1195
Research Manager
Administrative Manager

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