Bifunctional signaling proteins

Credit: Kenneth Eward / Photo Researchers, Inc" /> Credit: Kenneth Eward / Photo Researchers, Inc The paper: S. Shenoy et al., "β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor," J Biol Chem, 281:1261-73, 2006. (Cited in 50 papers) The finding: In 2005, while screening for G protein-independent arrestin signaling on the widely studied ERK pathway, Robert Lefkowitz's group at Duke University

Jan 1, 2008
Andrea Gawrylewski
<figcaption> Credit: Kenneth Eward / Photo Researchers, Inc</figcaption>
Credit: Kenneth Eward / Photo Researchers, Inc

The paper:
S. Shenoy et al., "β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor," J Biol Chem, 281:1261-73, 2006. (Cited in 50 papers)

The finding:
In 2005, while screening for G protein-independent arrestin signaling on the widely studied ERK pathway, Robert Lefkowitz's group at Duke University showed that β-arrestin can activate the β2-adrenergic receptor (β2AR), a receptor previously found only to be suppressed by arrestin.

The strategy:
The team blocked the G protein-dependent portion of the signaling pathway by using three separate inhibitors, in addition to knocking out G protein coupling. This paper exhaustively demonstrated that "arrestin clearly is capable of activating ERK" by signaling the β2AR pathway, says Jeffrey Benovic at Thomas Jefferson University in Philadelphia, and former protégé of Lefkowitz.

The follow up:
Lefkowitz and others are now looking at the physiologic differences that result from the separate signaling pathways. For example, Lefkowitz says, both pathways can regulate the mitogen-activated protein kinase (MAPK), but the outcome is different for each: One translocates MAPK to the nucleus; the other in the cytoplasm.

The application:
Lefkowitz's team recently showed that the cardiac drug carvedilol blocked G protein-dependent signaling while enhancing arrestin activity (Proc Natl Acad Sci, 104:16657-62, 2007). "Some specific ligands for receptors can selectively activate [the] G protein pathway or [the] arrestin side of the pathway," says Benovic. "That can give us a unique way of targeting a receptor pharmacologically."

Other G protein-dependent pathways activated by β-arrestin:
Chemotaxis: Mol Pharm, 67:1229-36, 2005
β1AR (via ERK MAPK signaling): J Clin Invest, 117:2445-58, 2007
Actin cytoskeletal assembly: J Biol Chem, 282:20634-46, 2007