Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Bound for destruction

29.12.2004


Ubiquitination protects against improper Notch signaling



The Notch pathway is an important molecular signaling mechanism whose existence has been known, or at least hinted at, for nearly a century since the identification of a mutant strain of Drosophila fruit flies with "notched" wings in Thomas Hunt Morgan’s lab in 1910. Later studies revealed that the Notch gene encodes a receptor protein that extends through both sides of the cell membrane and which is capable of interacting with a ligand partner, such as the protein Delta, presented on the surface of a neighboring cell. This "juxtracrine" interaction causes the cleavage of an intracellular region of the Notch protein, loosing it into the cytoplasm and triggering the activation of transcription factors within the cell’s nucleus. In addition to its effects on wing structure in flies, Notch signaling is known to be important in a number of neural cell fate determination and developmental processes, and is conserved in species from human to roundworm. In all processes in which it participates, Notch signaling shows the ability to sense a small change in cell fate and amplify it, acting as a sort of contrast enhancement mechanism in cell fate determination.

Notch is activated by a protease that is present ubiquitously in the cell membrane. What has long remained a mystery, however, is the question of how Notch receptors that have not been activated by a ligand are protected from digestion by that protease. Now, in a report published in the December 29 issue of Current Biology, Shigeo Hayashi (Group Director, Laboratory for Morphogenetic Signaling) and colleagues at the RIKEN Center for Developmental Biology (Kobe, Japan) have identified the means by which unstimulated cells protect the Notch receptor from activation.


Recent studies by other labs had shown that a number of stages in the Notch cascade were subject to ubiquitination, in which proteins are tagged by a complex of ubiquitin proteins. This system is best known for its function in marking proteins for degradation by a waste disposal unit known as a proteasome. Hayashi et al. sought to study the possibility that ubiquitination might play a part in rendering the unbound Notch receptor inert. Their attention was drawn to Nedd4 (a member of the ubiquitin ligase family of molecules that directly bind to proteins marked for degradation), as it had previously been shown that Nedd4 plays a role in the processing of other types of transmembrane proteins. Proteins in the cell membrane must first be internalized through a process known as endocytosis before they can be digested by the proteasome, and indeed other types of ubiquitin ligase have been shown to operate in the endocytosis of ligand-activated Notch.

The group first showed that an increase in nedd4 activity resulted in the nicked wing phenotype characteristic of Notch loss of function and in reductions of the total amount of the Notch intracellular domain in the cytoplasm of treated cells. Taken together, these results suggested that Nedd4 works as an antagonist of Notch signaling at an early stage, prior to the proteolytic cleavage of the receptor’s intracellular domain. Further investigation revealed the specific domain by which Nedd4 interacts with Notch and pinpointed the site of origin for this interaction at the cell membrane, a finding congruent with the idea of Nedd4 as an agent of endocytosis. Nedd4’s role as a suppressor of Notch was illustrated even more plainly when the lab showed that inhibition of Nedd4 results in the upregulation of ligand-independent activation of the Notch pathway.

Nedd4’s place in the greater scheme of Notch signaling became clearer when the group next turned to examine the interaction between Nedd4 and Deltex (Dx), a putative ubiquitin ligase known to bind and activate the Notch receptor. Hayashi’s group found evidence that Nedd4 and Dx vie with each other to regulate Notch activity during endocytosis, and that Nedd4 actually destabilizes Dx in the presence of Notch. This competition between two ubiquitin ligases to permit or suppress activation of a signaling pathway represents a neat solution to the problem confronting cells of how to prevent molecular loose cannons from fouling their precisely ordered workplans.

Doug Sipp | EurekAlert!
Further information:
http://www.cdb.riken.jp

More articles from Life Sciences:

nachricht A new molecular player involved in T cell activation
07.12.2018 | Tokyo Institute of Technology

nachricht News About a Plant Hormone
07.12.2018 | Julius-Maximilians-Universität Würzburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

Im Focus: Three components on one chip

Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.

Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...

Im Focus: Substitute for rare earth metal oxides

New Project SNAPSTER: Novel luminescent materials by encapsulating phosphorescent metal clusters with organic liquid crystals

Nowadays energy conversion in lighting and optoelectronic devices requires the use of rare earth oxides.

Im Focus: A bit of a stretch... material that thickens as it's pulled

Scientists have discovered the first synthetic material that becomes thicker - at the molecular level - as it is stretched.

Researchers led by Dr Devesh Mistry from the University of Leeds discovered a new non-porous material that has unique and inherent "auxetic" stretching...

Im Focus: The force of the vacuum

Scientists from the Theory Department of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science (CFEL) in Hamburg have shown through theoretical calculations and computer simulations that the force between electrons and lattice distortions in an atomically thin two-dimensional superconductor can be controlled with virtual photons. This could aid the development of new superconductors for energy-saving devices and many other technical applications.

The vacuum is not empty. It may sound like magic to laypeople but it has occupied physicists since the birth of quantum mechanics.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

Expert Panel on the Future of HPC in Engineering

03.12.2018 | Event News

Inaugural "Virtual World Tour" scheduled for december

28.11.2018 | Event News

 
Latest News

A new molecular player involved in T cell activation

07.12.2018 | Life Sciences

High-temperature electronics? That's hot

07.12.2018 | Materials Sciences

Supercomputers without waste heat

07.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>