No. 3/ February 14, 2002
Hakai – the Destroyer
MDC Cell Biologists make New Discovery
What holds cells together and what allows them to break free
of their normal environment? These questions play key roles in the development
of all living organisms as well as in the development of metastases in some
cancers. They have intrigued molecular and cell biologists for many years. The
research group of Prof. Walter Birchmeier from the Max Delbrück Center for
Molecular Medicine (MDC) Berlin-Buch has been studying molecules which bind
cells to one anoother like cement, the so-called adhesion molecules. The
researchers have also been able to identify molecules which can “dissolve” this
cell cement, turning cells into vagabonds. Now Dr. Yasuyuki Fujita and Prof.
Birchmeier have discovered a new molecule which not only breaks down the cell
cement but also ensures that important cell anchors are dismantled at the same
time. Dr. Fujita and Prof. Birchmeier have called their molecule ”Hakai”, after
the Japanese word for destruction. The MDC researchers findings in
collaboration with researchers from the Forschungsinstitut für Molekulare
Pharmakologie (FMP, also in Berlin-Buch) and from the Universities of
The Hakai molecule discovered by the MDC researchers binds to the adhesion molecule E-cadherin in epithelial cells. E-cadherin is a transmembrane protein, which means that it is able to cross the cell membrane and reach into the inner regions of the cell. Once there, it is tightly anchored to another binding molecule, beta-catenin (lat. catena – a chain). Epithelial cells coat the surface of the body and its internal tissues, among them skin cells, mammary cells, the cells of the mouth and pharyngeal space, gastrointestinal tract, pancreas, kidneys and sex organs.
Over 90 per cent of malignant tumours are formed from epithelial cells. If the cell loses its E-cadherin, it can develop into a mesenchymal, connective tissue-type cell. This cell is then able to travel to almost any part of the body. It takes on an invasive character, entering other tissues. ”This is an initial important step in the occurrence of a tumour”, said Prof. Birchmeier explaining this event. However, the ability of epithelial cells to transform themselves into mesenchymal cells plays an important role not only in the formation of carcinomas but also in the development of all living organisms.
Hakai attaches itself to E-cadherin if this adhesion molecule is activated by certain enzymes, the so-called tyrosine kinases, the researchers have found out. They call this process phosphorylation. In this particular case, it simply means that Hakai labels E-cadherin and the associated beta-catenin. This disrupts the contact between the cell and other epithelial cells. Then, in a second step, Hakai summons up the control system for proteins in the cells. This ubiquitin system identifies the adhesion molecules as being no longer of satisfactory quality and destroys them.
This quality control system normally ensures that altered and defective proteins in the body cannot cause any damage. Obviously, this system is of fundamental importance as far as maintaining the organism in a healthy state is concerned. A typical example of this is baker’s yeast, a very simple organism, which has survived for millions of years. For this reason, researchers claim that results obtained in experiments on baker’s yeast can be extrapolated to higher organisms.
The function of E-cadherin in the development of carcinomas has been the subject of intensive research. According to Prof. Birchmeier, ”Hakai may actually be an oncogene which, when it undergoes a change, can transform a healthy cell into a tumour cell in a number of steps, which leads to the destruction of the cell-cell contact triggering the cancer cell to form metastasis.” The MDC cell biologists now want to see if Hakai exhibits increased activity in human tumour cells and acts as an oncogene.
*Hakai,
a c-cbl-like protein, ubiquitinates and induces endocytosis of the E-Cadherin
complex Yasuyuki
Fujita1,5, Gerd Krause2, Martin Scheffner3,
Dietmar Zechner1, Hugo E. Molina Leddy1, Jürgen Behrens1,4,
Thomas Sommer1 and Walter Birchmeier1,6 1Max-Delbrück-Center
for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 2Forschungsinstitut fuer
Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, 13125 Berlin, Germany 3University
of Köln, 4Present address: University of
Erlangen, Nikolaus-Fiebiger-Center, Glueckstr. 6, 91054 Erlangen, Germany e-mail: 5fujita@mdc-berlin.de
or 6wbirch@mdc-berlin.de
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
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