Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How the tilt of a cell-surface receptor prevents cancer

01.02.2013
Clear communication between cells is essential to every aspect of the body's internal function. But since cells can't talk, or send emails, how do they communicate?

The answer, in a nutshell, is by dispatching signaling molecules that selectively bind to protein receptors on the outer surface of other cells with which they must "talk."

This activates the tail end of such receptors inside the cell, initiating a cascade of enzymatic reactions, or signaling pathways that reach into the nucleus, turning genes on and off. All such signaling is tightly regulated, and mutations that permanently activate certain receptors can drive the uncontrolled proliferation of cells, a defining characteristic of cancers.

In a paper published this week in the Proceedings of the National Academy of Sciences, a team led by Ludwig researcher Stefan Constantinescu, MD PhD, in Brussels based at the de Duve Institute, Université catholique de Louvain and Steven Smith, PhD, of Stony Brook University in New York shows how a mutation that alters a single amino acid in the thrombopoietin receptor turns it on permanently, explaining how it leads to the blood malignancies essential thrombocythemia (ET) and primary myelofibrosis.

"The thrombopoietin receptor is important in hematopoiesis, or the formation of blood," says Constantinescu. "It is activated by a factor known as thrombopoietin, and is required for the wellbeing of stem cells in the bone marrow and the generation of platelets, which are involved in clotting." A mutation that continuously turns on the signaling pathway it controls has been shown to lead to certain kinds of blood cancer. But some forms of ET and primary myelofibrosis do not bear that mutation.

In 2006, Constantinescu's lab identified a unique chain of five amino acids at the bottom of a coiled portion of the thrombopoietin receptor (TpoR) that traverses the membrane. They subsequently showed that a mutation of one of those amino acids—known as tryptophan, and symbolized by the letter W—found at position 515, led to the receptor's permanent activation in mice. Constantinescu and his colleagues predicted then that mutations of W515 would turn up in human cancers—and were proved correct by other laboratories and their own studies. "But what remained unclear for the field," says Constantinescu, "was why this tryptophan in particular is so important, why, if you mutate it, TpoR is spontaneously activated."

Biochemical and functional analyses of mutant and normal TpoR conducted by Constantinescu's lab and structural studies of receptors conducted by Smith's lab, established that the tryptophan has a pronounced effect on the function of TpoR through control of the receptor's spatial orientation. "Basically, we found that the tryptophan forces TpoR to tilt," says Constantinescu. "This means that when two normal TpoRs that have not yet been switched on by thrombopoietin come together in the cellular membrane, the tilted coils that normally span the membrane cross each other to form something like an X, not two parallel lines. When parallel, these coils attract each other specifically. Tilting prevents the two coils from contacting each other within the membrane and, in effect, prevents their spontaneous activation."

"If you replace the tryptophan with a variety of amino acids other than tryptophan," explains Constantinescu, "the receptor straightens up. It can then pair up with another TpoR—even without thrombopoietin binding—and begin signaling continuously." The result, it would appear, is the unrestrained transmission of proliferative signals and the development of ET and primary myelofibrosis.

This finding is significant for both the basic science of signal transduction and applied cancer research. Tryptophan is found at similar points in some other cell surface receptors, but molecular biologists had presumed that its main function was as a marker for the point at which the receptor emerges from membrane into the cell's cytoplasm. "We think these tryptophans may be more than just border markers, that they may generally prevent the spontaneous activation of some receptors by impairing the close apposition of membrane coils," says Constantinescu. He and his colleagues have begun bioinformatics studies to test this hypothesis—and determine if similar mutations on other single-pass receptors are also associated with cancer.

The current findings could have implications for cancer drug development as well. Constantinescu's lab has already established a partnership with a group at the Experimental Therapeutics Center in Singapore to develop experimental methods to rapidly evaluate the ability of small molecules to force membrane-embedded coils of mutated TpoR to return to their normal, tilted position. "Such molecules," says Constantinescu, "could have some potential as cancer therapeutics."

Financial support for this research was received from National Institutes of Health Grant GM-46732 (to S.O.S.); a FRIA doctoral fellowship Q:25 (to J.-P.D.); a de Duve Institute Delori postdoctoral fellowship (to V.G.); de Duve Institute and FNRS fellowships (to C.P.); the FRS-FNRS and FRSM, Belgium; the Salus Sanguinis Foundation; the ARC MEXP31C1 and ARC10/15-027 program of the Université catholique de Louvain; the Fondation contre le Cancer; the Belgium IAP Program, de Duve Institute and the Ludwig Institute for Cancer Research Ltd. (S.N.C).

About the Ludwig Institute for Cancer Research

The Ludwig Institute is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, the Institute is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Institute has spent more than $1.5 billion on cancer research. http://www.licr.org

For further information please contact Rachel Steinhardt.

Rachel Steinhardt | EurekAlert!
Further information:
http://www.licr.org

More articles from Life Sciences:

nachricht Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie

nachricht Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Molecular Force Sensors

20.09.2017 | Life Sciences

Producing electricity during flight

20.09.2017 | Power and Electrical Engineering

Tiny lasers from a gallery of whispers

20.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>