Proteins that stop a major signaling pathway can also generate new proteins

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Proteins that stop a major signaling pathway can also generate new

proteins

http://www.eurekalert.org/pub_releases/2008-04/dumc-pts042408.php

DURHAM, N.C. – Duke University Medical Center researchers have

recently discovered that a crucial communications pathway in cells

not only stops cells from making proteins, it also makes them go. The

team was able to define the way in which proteins called beta

arrestins (for their role in stopping signals) also turn on pathways

that ultimately lead to the production of new proteins in virtually

all tissues in the body.

Because proteins are the building blocks for all cells, this new

pathway for the general control of protein manufacturing has opened a

new universe for biological studies.

The beta arrestins were discovered two decades ago as the off

switches for G protein-coupled receptors (GPCRs) on the cell surface,

which do the job of sending and receiving important signals for

cells. This mechanism is the target of about a third of all

pharmaceuticals today.

The GPCRs, which were first theorized and discovered at Duke by the

study's senior author, J. Lefokowitz, MD, begin a signaling

cascade that transmits a message from the cell surface, such as a

hormone or neurotransmitter, to the cell's interior and tells it to

do something, such as cranking out a particular protein.

These receptors regulate virtually all physiological processes,

everything from heart rate to mood. Research on GPCRs has led to

numerous successful drugs, including beta blockers which help relieve

hypertension, angina and coronary disease, as well as new

antihistamines and ulcer drugs. They also formed the basis of Nobel

Prize winning work on smell receptors.

" The reason the new work is so exciting to me is that it reminds us,

yet again, how the scientific process continuously renews itself,

said Lefkowitz, B. Duke Professor of Medicine and investigator

of the Medical Institute. " We discovered the beta

arrestins almost 20 years ago, and now we find out they play

signaling roles we never dreamed of back then. We are hopeful that

these new ideas may lead to new types of drugs. "

The study's findings, published in this month's Journal of Biological

Chemistry, identified an enzyme called Mnk1 which is activated by

beta-arrestin signaling. " What's been discovered here is that beta

arrestins initiate important cell signals in their own right, and

specifically the control over protein synthesis indicates that they

may possess wide control of biological functions, " said DeWire

PhD, lead author and adjunct assistant professor of medicine at Duke

University.

" This added layer of complexity provides us opportunities to study

receptors in a whole new way, and possibly identify beta-arrestin-

specific signaling, " DeWire said. " This is something completely

unexpected according to the traditional dogma. Ten years ago, nobody

would have imagined that beta-arrestins, with their ability to stop

the GPCR signals, could exert global control over protein synthesis. "

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Other authors of the paper include Jihee Kim, PhD, J. Whalen,

PhD, and Minyong Chen, PhD, of the Duke Department of Medicine and

Seungkirl Ahn, PhD, who works in the Medical Institute

at Duke University Medical Center.