Proteins on Demand

Any far-flung empire needs outposts on its boundaries, allowing the realm to stay in touch with changing conditions and respond quickly without waiting for messages and supplies from distant headquarters. Likewise, a cell must monitor signals that reach its borders and may need to react rapidly and locally.

A new study of neurons reveals such a shortcut to the traditional view of how cells respond to outside signals. Researchers discovered protein synthesis machinery directly linked with a cell surface receptor that tells the tips of axons when to grow and which way to turn. The setup may allow just-in-time protein-making at specific locations.

Published online April 28 in Cell, the findings mean that scientists must consider a new way that cells may organize themselves to perform essential functions. “The cell surface receptor can associate directly with the protein synthesis machinery,” said senior author John Flanagan, HMS professor of cell biology. “It’s a principle you might expect would apply to different types of cells and different receptors.”

The discovery offers a new way of looking at receptors and molecular responses inside all cells. Typically, scientists portray an activated receptor as touching off a series of molecular interactions known as a signal transduction cascade. Imagine a string of molecular conversations stretching from a surface receptor deep into the cell, to the nucleus where genes extrude the messenger RNA, and to the protein-making machinery of the ribosomes; these are usually thought to be located well inside the cell near the nucleus or floating in the cytoplasm.

“In the standard view,” Flanagan said, “when receptors on the cell surface receive an outside signal, they may regulate the production of new proteins by relaying the signal to the interior of the cell through complicated pathways that reach the ribosomes, where proteins are made. The traditional view is that these ribosomes are located either on the endoplasmic reticulum or in the cytoplasmic fluid,” he said.

“We’re not saying the traditional view is wrong,” Flanagan said. “Our concept is that there is a particle where protein-making machinery is bound to the inside of a membrane receptor. The ribosome associates directly in a complex with the cell surface receptor.”

Led by co–first authors Joseph Tcherkezian and Perry Brittis, the research team’s original scouting experiment revealed strategically positioned outposts for making proteins on demand and on-site. The receptor investigated in this study, called DCC, helps guide the growing tip of developing neurons in the correct direction in response to an outside factor, a process that requires new proteins to be made at the axon tip.

“The protein-synthesis machinery was localized to the site of incoming messages from the receptor,” said Tcherkezian, a postdoctoral fellow. “This may be a widespread phenomenon, one involving many receptors. A growing body of evidence supports local translation of proteins in many different parts of the cell.”

In related emerging evidence, some research groups have found messenger RNA stashed in multiple locations all around the cell, presumably waiting for signals to switch on the translation of mRNA into proteins. A large amount of work shows, for example, that local synthesis of proteins is important in strengthening brain connections, also known as synapse plasticity, underlying learning and memory.

“Localization of protein synthesis within the cell is a rising concept,” Flanagan said. His group’s work adds a potential mechanism for making proteins on-site from mRNA, a process scientists call “translational control.”

“We have a mechanism that may provide that localization,” said Flanagan. “Our study is about the location of the machinery and, even more important, the potential to activate translation in very specific places, in response to some extracellular cue.”

For more information, students may contact John Flanagan at flanagan@hms.harvard.edu.

Conflict Disclosure: The authors declare no conflict of interest.

Funding Sources: The National Institutes of Health; the authors are solely responsible for the content of this work.