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Decoding Covert Cell Signals

Ashley Yeager

A new method makes it easier to study how cells talk to each other through protein secretion. How? Find out...

Like clicks in Morse code, secreted proteins transmit information between different cells. Deciphering these messages has been very challenging for scientists. But now, a team from Germany's Max Planck Institute has use liquid chromatography mass spectrometry (LC-MS) to achieve quantitative, high-resolution detection of hundreds of proteins released by a small number of immune cells.

The new protein detection technique could help identify more of the ones cancer cells secrete. Credit: Gopal Murti, Photo Researchers, Inc.

"Our technique provides an unbiased picture of the proteins that cells secrete to communicate with each other upon activation," said Felix Meissner, lead author of a paper in the April 26 issue of Science that describes the new method (1).

Although scientists have studied secreted proteins before, existing methods based on labeling proteins with antibodies are limited by the availability and efficiency of those antibodies. In addition, antibody-based approaches are also relatively expensive. In contrast, the LC-MS workflow developed by Meissner and colleagues allows for cheaper, more efficient protein analyses.

To test their method, the team analyzed how immune cells respond to pathogens by exposing mouse macrophages to a bacterial molecule in order to trigger an inflammatory response. Using the new technique, they detected and quantified nearly 800 proteins that were secreted by the macrophages. Some of the identified proteins weren’t known to work outside of cells.

"We were very surprised by the fact that known secreted proteins such as interleukins, cytokines, and growths factors comprise only a minority of the secreted protein content," Meissner said. "Given that in biology many things happen for a good reason, this observation could imply that there are potentially many more proteins with extracellular functions."

To study the connection between protein secretion and protein signaling, the team generated versions of the mouse immune cells that were missing one of two adaptor proteins: MyD88 or TRIF. They found that if both MyD88 and TRIF can individually transmit a signal, they often share the workload, providing a redundancy during the initiation of the inflammatory response. But to turn off the response, the two adaptors must act together to release anti-inflammatory proteins. When one of the two adaptors is missing, the inflammatory response proceeds as normal but the later anti-inflammatory response does not.

"While doing this, it became apparent that among the synergistically secreted proteins were many proteins with anti-inflammatory functions, whereas this was not the case for redundantly released proteins," he said.

In the end, Meissner believes that the new LC-MS workflow will help other researchers studying secreted proteins to decipher cell-to-cell signaling in a variety of cell types.


1. Meissner, F., R. A. Scheltema, H.-J. Mollenkopf, and M. Mann. 2013. Direct proteomic quantification of the secretome of activated immune cells. Science 340(6131):475-478.

Keywords:  cell signaling