Cancer cells need life-essential molecules to proliferate. These growth factors are activated by ectodomain shedding of precursor proteins on the outside of plasma membrane, mainly carried out by three human cleavage enzymes. A pharmaceutical blocking of these enzymes could hinder cancer from growing but would also inhibit other life-essential processes.
Researchers from German Leibniz Institute for Age Research and Harvard University, US, showed that the factor-precursor-producing cells themselves define if cleavage may occur. This is decided by intracellular signaling. Interfering with defined signaling in cells producing cancer growth factors could lead to a new way of cancer treatment.
License for cutting: Factor-precursor-producing cells determine if and when ectodomain cleavage may occur to activate growth factors.
[Graphic: Liseth M Parra / FLI]
As cancer cells proliferate in an unlimited way, they need to be supplied with oxygen and nutrients. For their growth and the formation of blood vessels, so-called growth factors are required. These hormone-like proteins are activated by the shedding of transmembrane precursor proteins that have to be cleaved on the outside of the plasma membrane by specialized enzymes.
In the human body, mainly three “cleavage enzymes” are responsible for ectodomain shedding of hundreds of growth factors. Hindering one of these enzymes from cleaving would certainly suppress the production of growth factors related to tumorigenesis, but would have severe side-effects: a lot of life-essential molecules would also be inhibited. Since ectodomain cleavage is highly important for homeostasis of the organism, it needs to be tightly regulated with respect to both its overall abundance and time course.
Now, in a collaborative project, researchers from German Leibniz Institute for Age Research (FLI) in Jena and renowned Harvard University in Cambridge, US, showed that obviously the precursor proteins themselves dictate if and when the “scissor”-enzymes may cut. Signal processing in the intracellular domain of the precursor-protein-producing cells is responsible for modifications that likely induce a relative positional change of the dimerization partners and, in the end, allow cleavage.
This is individually different for each precursor protein. The collaborators from Jena and Cambridge already found many details of the mechanism to explain how the intracellular domain modification communicates with the ectodomain of the substrate to allow for cleavage to occur, e.g. releasing growth factors linked to breast cancer (Epidermal Growth Factor family) and Neuregulin which is important for neuro-regeneration, as well as cleavage of a protein relevant for metastasizing of cancer cells. The latest publication in the "Journal of Biological Chemistry" now was nominated as one of the best 50 out of this year’s 6.000 publications.
“Our research results offer a new way of suppressing growth factors related to cancer cell proliferation”, Prof. Dr. Peter Herrlich, former scientific director and now associated researcher at FLI, explains. Instead of blocking the cleavage enzymes and condoning side-effects, the intracellular signal processing for single precursor proteins may be inhibited in order to specifically knock out the growth factors required by individual cancer types.
Hartmann M, Parra LM, Ruschel A, Lindner C, Morrison H, Herrlich A, Herrlich P. Inside-out Regulation of Ectodomain Cleavage of Cluster-of-Differentiation-44 (CD44) and of Neuregulin-1 Requires Substrate Dimerization. Journal of Biological Chemistry (2015), DOI 10.1074/jbc.M114.610204.
Dr. Evelyn Kästner
Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI)
Beutenbergstr. 11, D-07745 Jena
Tel.: +49 3641-656373, Fax: +49 3641-656351, E-Mail: firstname.lastname@example.org
The Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI) is the first German research organization dedicated to biomedical aging research since 2004. More than 330 members from over 30 nations explore the molecular mechanisms underlying aging processes and age-associated diseases. For more information, please visit http://www.fli-leibniz.de.
The Leibniz Association connects 89 independent research institutions that range in focus from the natural, engineering and environmental sciences via economics, spatial and social sciences to the humanities. Leibniz Institutes address issues of social, economic and ecological relevance. They conduct knowledge-driven and applied basic research, maintain scientific infrastructure and provide research-based services. The Leibniz Association identifies focus areas for knowledge transfer to policy-makers, academia, business and the public. Leibniz Institutes collaborate intensively with universities – in the form of “WissenschaftsCampi” (thematic partnerships between university and non-university research institutes), for example – as well as with industry and other partners at home and abroad. They are subject to an independent evaluation procedure that is unparalleled in its transparency. Due to the institutes’ importance for the country as a whole, they are funded jointly by the Federation and the Länder, employing some 18,100 individuals, including 9,200 researchers. The entire budget of all the institutes is approximately 1.64 billion EUR. See http://www.leibniz-association.eu for more information.
http://www.fli-leibniz.de - Website Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI) Jena
Dr. Kerstin Wagner | idw - Informationsdienst Wissenschaft
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering
06.12.2016 | Power and Electrical Engineering