Jigsaw a critical piece of the Notch puzzle

Nov 29, 2012

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.

"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 and currently a postdoctoral fellow in the laboratory of Dr. Hugo Bellen, director of the Program in Developmental Biology and professor of molecular and 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 (CADASIL), a hereditary stroke disorder; Alagille syndrome, a 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.

"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."

Explore further: Researchers successfully clone adult human stem cells

Related Stories

Notch-ing glucose into place

Jan 27, 2008

A novel gene called rumi regulates Notch signaling by adding a glucose molecule to the part of the Notch protein that extends outside a cell, said researchers from Baylor College of Medicine in Houston and Stony Brook University ...

Feedback loop maintains basal cell population

Nov 01, 2012

Notch – the protein that can help determine cell fate – maintains a stable population of basal cells in the prostate through a positive feedback loop system with another key protein – TGF beta (transforming growth factor ...

Key growth factor identified in T cell leukemia

Aug 01, 2011

Blocking a growth factor receptor cripples cancer growth in a form of T cell leukemia, according to a study published online on August 1 in the Journal of Experimental Medicine.

Recommended for you

Researchers successfully clone adult human stem cells

14 hours ago

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Researchers develop new model of cellular movement

17 hours ago

(Phys.org) —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

For resetting circadian rhythms, neural cooperation is key

Apr 17, 2014

Fruit flies are pretty predictable when it comes to scheduling their days, with peaks of activity at dawn and dusk and rest times in between. Now, researchers reporting in the Cell Press journal Cell Reports on April 17th h ...

User comments : 0

More news stories

Researchers successfully clone adult human stem cells

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Male monkey filmed caring for dying mate (w/ Video)

(Phys.org) —The incident was captured by Dr Bruna Bezerra and colleagues in the Atlantic Forest in the Northeast of Brazil.  Dr Bezerra is a Research Associate at the University of Bristol and a Professor ...

Researchers develop new model of cellular movement

(Phys.org) —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

Impact glass stores biodata for millions of years

(Phys.org) —Bits of plant life encapsulated in molten glass by asteroid and comet impacts millions of years ago give geologists information about climate and life forms on the ancient Earth. Scientists ...