Featured Research

from universities, journals, and other organizations

Jigsaw a critical piece of the Notch puzzle

Date:
November 29, 2012
Source:
Baylor College of Medicine
Summary:
The Notch signaling pathway helps determine cell fate determination, differentiation and proliferative ability of numerous cells. How it accomplishes these tasks has been a puzzle, but researchers have identified a key piece -- a specific domain within the Notch receptor that is critical for determining the specific ligand to which the receptor binds.

The Notch signaling pathway helps determine cell fate determination, differentiation and proliferative ability of numerous cells. How it accomplishes these tasks has been a puzzle, but researchers led by those at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital have identified a key piece-a specific domain (or part of the receptor) within the Notch receptor that is critical for determining the specific ligand to which the receptor binds. The finding provides researchers with a molecular handle on which to base future studies of this critical protein.

A report on their work appears online in the journal Science.

Misregulation of Notch signaling is seen in various types of cancers and numerous human diseases. The Notch receptor can be activated by binding to two families of ligands, Serrate and Delta. Since different ligands can have different consequences on signal activation depending on the context, understanding how Notch discriminates Serrate and Delta is crucial. Most of the Notch receptor is composed of what scientists call EGF repeats (epidermal growth factor-like repeats). Previous studies have suggested that the key lies within these repeats.

Significance of EGF repeats

"We don't know the function of most of these EGF repeats on Notch," said Dr. Shinya Yamamoto, a former graduate student from the Program in Developmental Biology and currently a postdoctoral fellow in the laboratory of Dr. Hugo Bellen, director of the Program in Developmental Biology and professor of molecular and human genetics and neuroscience at BCM. "There are 36 of them. Some are needed to bind to both of the ligand families, while others are required to bind to only one kind." Indeed, mutations in these repeats have been found in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a hereditary stroke disorder; Alagille syndrome, a genetic disorder that affects the liver, heart, skeleton, eye and other organs; aortic valve disease, and squamous cell carcinoma.

In studies in fruit flies (Drosophila melanogaster), Yamamoto and his colleagues screened for mutated alleles (alternative forms of a gene) of Notch and focused on a mutation that they named Jigsaw. Flies with this mutation have normal bristles on the thorax but defects in the wing. They showed that the Notch gene exhibits defects in its ability to bind to Serrate but not Delta. They also showed that a similar mutation in mouse Notch2 fails to signal in response to Jagged, the mammalian homolog of Serrate.

Jigsaw mutation

"Structural biologists will now have a molecular handle with which to begin investigating the molecular basis of ligand selectivity at the atomic level," said Yamamoto. "Others may consider EGF repeat 8 as a potential drug target for small molecules and monoclonal antibodies."

Others who took part in this study include Wu-Lin Charng; Manish Jaiswal; Vafa Bayat; Bo Xiong; Ke Zhang; Hector Sandoval; Gabriela David and Hao Wang, all of BCM; and Robert Haltiwanger, Nadia Rana and Shinako Kakuda, all of Stony Brook University, Stony Brook, NY.

Funding for this work came from the National Institutes of Health; the BCM Intellectual and Developmental Disabilities Research Center; the Nakajima Foundation; the Taiwan Merit Scholarships Program of the National Science Council; the Edward and Josephine Hudson Scholarship Fund; the Houston Laboratory and Population Science Training Program in Gene-Environment Interaction of the Burroughs Wellcome Fund; and the Houston Research Education and Career Horizon Institutional Research and Academic Career Development Award.


Story Source:

The above story is based on materials provided by Baylor College of Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. Yamamoto, W.-L. Charng, N. A. Rana, S. Kakuda, M. Jaiswal, V. Bayat, B. Xiong, K. Zhang, H. Sandoval, G. David, H. Wang, R. S. Haltiwanger, H. J. Bellen. A Mutation in EGF Repeat-8 of Notch Discriminates Between Serrate/Jagged and Delta Family Ligands. Science, 2012; 338 (6111): 1229 DOI: 10.1126/science.1228745

Cite This Page:

Baylor College of Medicine. "Jigsaw a critical piece of the Notch puzzle." ScienceDaily. ScienceDaily, 29 November 2012. <www.sciencedaily.com/releases/2012/11/121129143306.htm>.
Baylor College of Medicine. (2012, November 29). Jigsaw a critical piece of the Notch puzzle. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2012/11/121129143306.htm
Baylor College of Medicine. "Jigsaw a critical piece of the Notch puzzle." ScienceDaily. www.sciencedaily.com/releases/2012/11/121129143306.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

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
Adorable Video of Baby Rhino and Lamb Friend Playing

Adorable Video of Baby Rhino and Lamb Friend Playing

Buzz60 (Oct. 20, 2014) Gertjie the Rhino and Lammie the Lamb are teaching the world about animal conservation and friendship. TC Newman (@PurpleTCNewman) has the adorable video! 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