Featured Research

from universities, journals, and other organizations

Bound For Destruction: Ubiquitination Protects Against Improper Notch Signaling

Date:
January 17, 2005
Source:
RIKEN Center For Developmental Biology
Summary:
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.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.

Adult Drosophila wing in which Nedd4 was overexpressed. Nedd4 inhibited wing margin formation and promoted expansion of the wing vein. The defects resemble the typical Notch mutant phenotypes.
Credit: Image courtesy of RIKEN Center For Developmental Biology

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.


Story Source:

The above story is based on materials provided by RIKEN Center For Developmental Biology. Note: Materials may be edited for content and length.


Cite This Page:

RIKEN Center For Developmental Biology. "Bound For Destruction: Ubiquitination Protects Against Improper Notch Signaling." ScienceDaily. ScienceDaily, 17 January 2005. <www.sciencedaily.com/releases/2005/01/050111165027.htm>.
RIKEN Center For Developmental Biology. (2005, January 17). Bound For Destruction: Ubiquitination Protects Against Improper Notch Signaling. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2005/01/050111165027.htm
RIKEN Center For Developmental Biology. "Bound For Destruction: Ubiquitination Protects Against Improper Notch Signaling." ScienceDaily. www.sciencedaily.com/releases/2005/01/050111165027.htm (accessed October 21, 2014).

Share This



More Plants & Animals News

Tuesday, October 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

'Cadaver Dog' Sniffs out Human Remains

'Cadaver Dog' Sniffs out Human Remains

AP (Oct. 21, 2014) Where's a body buried? Buster's nose can often tell you. He's a cadaver dog, specially trained to find human remains and increasingly being used by law enforcement and accepted in courts. These dogs are helping solve even decades-old mysteries. (Oct. 21) Video provided by AP
Powered by NewsLook.com
White Lion Cubs Born in Belgrade Zoo

White Lion Cubs Born in Belgrade Zoo

AFP (Oct. 20, 2014) Two white lion cubs, an extremely rare subspecies of the African lion, were recently born at Belgrade Zoo. They are being bottle fed by zoo keepers after they were rejected by their mother after birth. Duration: 00:42 Video provided by AFP
Powered by NewsLook.com
Traditional Farming Methods Gaining Ground in Mali

Traditional Farming Methods Gaining Ground in Mali

AFP (Oct. 20, 2014) He is leading a one man agricultural revolution in Mali - Oumar Diatabe uses traditional farming methods to get the most out of his land and is teaching others across the country how to do the same. Duration: 01:44 Video provided by AFP
Powered by NewsLook.com
Goliath Spider Will Give You Nightmares

Goliath Spider Will Give You Nightmares

Buzz60 (Oct. 20, 2014) An entomologist stumbled upon a South American Goliath Birdeater. With a name like that, you know it's a terrifying creepy crawler. Sean Dowling (@SeanDowlingTV) has the details. Video provided by Buzz60
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:

Strange & Offbeat Stories


Plants & Animals

Earth & Climate

Fossils & Ruins

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