Featured Research

from universities, journals, and other organizations

How the tilt of a cell-surface receptor prevents cancer

Date:
January 31, 2013
Source:
Ludwig Institute for Cancer Research
Summary:
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."

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, Universit้ 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 Universit้ 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).


Story Source:

The above story is based on materials provided by Ludwig Institute for Cancer Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. J.-P. Defour, M. Itaya, V. Gryshkova, I. C. Brett, C. Pecquet, T. Sato, S. O. Smith, S. N. Constantinescu. Tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1211560110

Cite This Page:

Ludwig Institute for Cancer Research. "How the tilt of a cell-surface receptor prevents cancer." ScienceDaily. ScienceDaily, 31 January 2013. <www.sciencedaily.com/releases/2013/01/130131121026.htm>.
Ludwig Institute for Cancer Research. (2013, January 31). How the tilt of a cell-surface receptor prevents cancer. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2013/01/130131121026.htm
Ludwig Institute for Cancer Research. "How the tilt of a cell-surface receptor prevents cancer." ScienceDaily. www.sciencedaily.com/releases/2013/01/130131121026.htm (accessed April 20, 2014).

Share This



More Plants & Animals News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Mich. Boy Unearths 10,000-Year-Old Mastodon Tooth

Mich. Boy Unearths 10,000-Year-Old Mastodon Tooth

Newsy (Apr. 20, 2014) — A 9-year-old Michigan boy was exploring a creek when he came across a 10,000-year-old tooth from a prehistoric mastodon. Video provided by Newsy
Powered by NewsLook.com
Vermont Goat Meat Gives Refugees Taste of Home

Vermont Goat Meat Gives Refugees Taste of Home

AP (Apr. 18, 2014) — Dairy farmers and ethnic groups in Vermont are both benefiting from a unique collaborative effort that's feeding a growing need for fresh and affordable goat meat. (April 18) Video provided by AP
Powered by NewsLook.com
Man Claims He Found Loch Ness Monster With... Apple Maps?

Man Claims He Found Loch Ness Monster With... Apple Maps?

Newsy (Apr. 18, 2014) — Andy Dixon showed the Daily Mail a screenshot of what he believes to be the mythical beast swimming just below the lake's surface. Video provided by Newsy
Powered by NewsLook.com
First Ever 'Female Penis' Discovered In Animal Kingdom

First Ever 'Female Penis' Discovered In Animal Kingdom

Newsy (Apr. 18, 2014) — Not only are these newly discovered bugs' sex organs reversed, but they also mate for up to 70 hours. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins