Scientists used to think most of the exchange of information between

cells was conducted at the surface, where cell receptors receive signals

from other cells.

Now Yale researchers report in the March 20 issue of the journal Cell

how a switching station beneath the cell surface is crucial to

processing signals from outside the cell. They also describe a key

molecular switch that terminates signaling from this station.

The findings portray a much more "complex and fluid system of

cellular information processing than previously envisioned", said Derek

K. Toomre, assistant professor of cell biology at Yale and co-author of

the study.

The Yale team was led by Pietro De Camilli, M.D., the Eugene Higgins

Professor of Cell Biology and Neurobiology. De Camilli is also an

investigator in the Howard Hughes Medical Institute, a member of the

Kavli Institute for Neuroscience and a director of the Yale Program in

Cellular Neuroscience, Neurodegeneration and Repair.

When information arrives at the cell surface, receptors that decode

this information are internalized by a process called endocytosis.

Typically endocytosis was viewed primarily as a mechanism to turn off

signaling within the cell. However, recent research has shown signaling

continues after internalization and that its strength and quality is

strongly influenced by molecular interactions within the cell.

The signaling location characterized in the study, referred to as an

APPL1 endosome, plays a key role early in this signaling process. The

Yale team identified a molecular switch: the generation of a fatty

component (a phosphoinositide) in the endosome membrane that triggers

progression of receptors and other cargo from APPL1 endosomes to other

intracellular destinations. Turning off this switch jams traffic in the

APPL1 endosomes and enhances signaling.

De Camilli first became interested in this novel endocytic

compartment when studying a protein that binds to the APPL1 endosome and

is involved in Dent disease, a rare genetic disease of the kidneys, and

in Lowe syndrome, a rare genetic disease of the eyes, the kidneys and

the brain.

"We expect that studies of APPL1 endosomes will not only advance our

understanding of basic mechanisms in cell physiology, but also give us

new insight about pathogenetic mechanisms and potential therapeutic

strategies in Lowe syndrome," De Camilli said.

Robert Zoncu and Rushika Perera, both postdoctoral associates at

Yale, were co first-authors of the study. Other Yale authors of the

paper are Daniel M. Balkin and Michelle Pirruccello.

The HHMI, the National Institutes of Health, the W.M. Keck

Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation and

the Kavli Foundation funded the work.

Source : Yale

University