Failure Of Protein Recycling System May Be Linked To Certain Diseases, Birth Def

[Guest guest]

Failure Of Protein Recycling System May Be Linked To Certain

Diseases, Birth Defects

http://www.medicalnewstoday.com/articles/92538.php

A group of signaling proteins known as Wnt - which help build the

human body's skin, bone, muscle and other tissues - depend on a

complex delivery and recycling system to ensure their transport to

tissue-building cell sites, according to a study at Cincinnati

Children's Hospital Medical Center. When the recycling system - the

Retromer Complex - breaks down, the delivery of this specialized

family of signaling proteins fails as their transport vehicle, a

cargo receptor called Wntless (Wls) becomes unstable and is

degraded. This important finding provides new insight into what may

be a mechanism behind cancer, heart disease or birth defects related

to Wnt proteins, researchers said.

Writing for the January 15, 2008 edition of Developmental Cell,

researchers at Cincinnati Children's studied the critical role that

a trafficking protein (called Vps35) has as the central assembly

platform of the Retromer Complex. This complex is made up of

trafficking proteins that act like cellular postmen to return a

cargo receptor, Wls, from cellular compartments called endosomes to

the Trans-Golgi Network. The network acts like a molecular clearing

house - packaging and sorting proteins for targeted delivery - and

the job of Wls is to deliver Wnt signaling proteins from Trans Golgi

to their intended tissue-building sites. If the Retromer Complex

fails to recycle Wls back to the Trans Golgi to do their job, it

thwarts stable delivery of Wnt signaling proteins.

" We know secreted Wnt proteins play essential roles in many

biological processes, including the development of diseases, but

very little is known about the mechanisms by which Wnt processing

and secretion are regulated, " said Xinhua Lin, Ph.D., a researcher

in the Division of Development Biology at Cincinnati Children's and

senior author of the study. " Our main finding in this study is that

the Retromer Complex is required for stable Wnt secretion, providing

new insights into how certain diseases work. "

In a series of experiments with genetically engineered cells from

the fruit fly Drosophila, mice and humans, Dr. Lin and his

colleagues mutated the Vps35 trafficking protein to compromise its

central assembly role in the Retromer Complex, then observed the

delivery cycle of Wnt proteins between the Trans-Golgi Network and

targeted cell sites. In all three series, the compromised Retromer

Complex resulted in Wnt protein accumulating in the Trans-Golgi

Network and Wls cargo receptors being degraded instead of returning

to the network and their job of delivering Wnt proteins.

" Although we propose that the Wls protein acts as a cargo receptor

for Wnt signaling proteins, we need to conduct more experiments to

further our understanding of this process, including how the Wls

delivers Wnt from the Trans-Golgi, " Dr. Lin said.

In their study, the researchers proposed a delivery cycle model

where Wnt initially enters the Trans-Golgi Network and binds with

the Wls cargo receptor, which then transports Wnt to targeted cell

surfaces. Once Wls has delivered Wnt proteins, one of two things

occurs, depending on whether the Retromer Complex is functioning

normally. When working as designed, the Retromer Complex retrieves

the spent Wls protein for return to the Trans-Golgi. When Retromer

Complex breaks down, Wls cargo receptor is absorbed into the cell's

lysosome, where it is digested and destroyed.