Cells can cut up rough: They will sometimes even gnaw at a partner in order to get rid of it as quickly as possible. This mechanism, known as trogocytosis (Greek: trogo, to gnaw), is important for cell sorting and plays a role in processes as diverse as embryonic development and the interaction between tumor and immune cells. Researchers have now discovered important factors that coordinate this special type of cell interaction.
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“Till death us do part” – cells don’t usually go to this extreme, but separation by trogocytosis does, in fact, involve a small amount of cannibalism.

An important way for cells to get in touch is the ephrin/Eph signaling pathway. The ephrin ligand in one cell (red in the graphic) binds with the Eph receptor in a neighboring cell (green). The neighboring cell then devours the relatively large receptor-ligand complex (yellow), virtually biting off its neighbor’s outstretched hand to enable separation. At least both cells survive the process, in contrast to phagocytosis.

The researchers found that this ephrin/Eph mediated trans-endocytosis resembles features of trogocytosis. “Trogocytosis is not well understood and different from phagocytosis, a well-studied process where one entire cell is eaten up by another”, relays Jingyi Gong from the Max Planck Institute of Neurobiology in Martinsried. “We wanted to decipher how trogocytosis is regulated.”

Trogocytosis is known to play an important role in the development of the nervous system. A better understanding of trogocytosis and linking it to ephrin/Eph could open the way for new regenerative therapies for injuries or diseases of the nervous system.
What is involved in this cell nibbling process?

The international team of researchers from Rüdiger Klein’s department and from the University of Toronto (Canada) used fluorescence microscopy to view trogocytosis in action and analyzed the proteins involved.

The researchers discovered that clusters of Gulp1, a protein familiar to phagocytosis, accumulate temporarily on the ephrin/Eph complex of both cells. Subsequently, the ephrin/Eph complex is devoured by the cells. Tiam2, a protein that stimulates the reorganization of the cytoskeleton, supports Gulp1 in this process. In addition, Gulp1 also recruits the protein dynamin, initiating the internalization process on the membrane.

“We could thus demonstrate that mechanisms which play a role in the ephrin/Eph trogocytosis overlap with those involved in phagocytosis,” explains Thomas Gaitanos, joint lead author of the study. The team now plans to investigate under what conditions trogocytosis can occur in the brain and whether this ability can be exploited for the regeneration of injured brain areas.

Jingyi Gong, Thomas N. Gaitanos, Olivia Luu, Yunyun Huang, Louise Gaitanos, Jana Lindner, Rudolf Winklbauer, and Rüdiger Klein (2019).
Gulp1 controls Eph/ephrin trogocytosis and is important for cell rearrangements during development. Journal of Cell Biology  218: 3455.
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When cells grow and divide, they come into contact with other cells. This happens not only during development and regeneration and after injury, but also during cancer growth and the formation of metastases. When cells come into contact with each other in this way, information is exchanged by proteins, which are embedded in the cell membranes and form tight lock-and-key complexes with each other. These connections must be severed if the cells want to transmit a repulsion signal. It appears that the fastest way to do this is for the cells to engulf the protein complex from the membrane of the neighboring cell. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now identified the molecules that control this process.

Development is an extremely rapid process. Increasing numbers of cells are formed which must find their correct position in the body, clearly demarcate themselves from each other to form tissue, or – as is the case in the nervous system – establish contact with partner cells in remote locations. “The crowding is accompanied by orderly pushing and shoving,” says Rüdiger Klein, whose Department at the Max Planck Institute of Neurobiology studies how cells get their bearings. “A popular way for one cell to show another which direction to take is for it to repel the other cell following brief contact.” According to the scientists’ observations, the cells do not exactly treat each other with kid gloves and even go so far as to engulf entire pieces from the membranes of other cells.

When cells come into contact with each other, ephrin and Eph receptors are often involved. These proteins are located on the surface of almost all cells. When two cells meet, their ephrin and Eph receptors connect to form tight ephrin/Eph complexes. These complexes then trigger the repulsion process through intracellular signaling pathways. “This is where the problem arises, as it appears that the cells then want to separate as quickly as possible – however, the two cells are attached to each other through the tight ephrin/Eph complex,” explains Klein. So the cells do something else: they extend their own cell membranes so far over the individual complexes that the complex and the surrounding membrane detaches from the neighboring cell and is fully incorporated into the cell.

Left: Ephrin and Eph receptors are found on the surface of almost all cells. Center: When cells come into contact with each other, the two proteins form a tight complex. This triggers a signaling chain which causes the cell membrane to protrude. This process is controlled by the Tiam and Rac molecules and results in the reformation of the actin cytoskeleton. Right: The cells separate when one cell fully engulfs the ephrin/Eph complex through endocytosis.
© MPI of Neurobiology/Gaitanos

The Max Planck researchers discovered as early as 2003 that cells can use this process, known as endocytosis, to separate from each other. Thanks to progress made in molecular biology since then, they have now managed to show how the process is controlled in detail.

With the help of a series of genetic modifications and the targeted deactivation of individual cell components, the scientists succeeded in demonstrating that Tiam signaling proteins are activated through the formation of the ephrin/Eph complex. As a result, Rac enzymes become active which, in turn, cause the engulfment of the ephrin/Eph complexes by the cell membrane through the local restructuring of the actin cytoskeleton. If one of these components is missing, this engulfing process through endocytosis is blocked and the cells do not repel each other but remain attached.

The clarification of this signaling pathway is important, as it provides a better understanding of the development of neuronal networks and other organ systems. The findings are also of considerable interest for cancer research: thanks to their ability to control cell repulsion, ephrin and Eph receptors play a major role in the penetration of tissue by cancer cells and in the formation of metastases. For this reason, receptors and their connection partners are the focus of current medical research. Better understanding of this signaling pathway, through which cell repulsion is controlled, could enable the development of new drugs to combat cancer.

Original Publication:
Thomas N. Gaitanos, Jorg Koerner, Rüdiger Klein
Tiam/Rac signaling mediates trans-endocytosis of ephrin receptor EphB2 and is important for cell repulsion.
Journal of Cell Biology; 5 September, 2016
https://dx.doi.org/10.1083/jcb.201512010

The post Hungry cells on the move first appeared on Max Planck Neuroscience.

Eph receptors and their partner proteins, the ephrins, are vital for intercellular communication. In the developing brain, they guide young neurons to the right partner cells by repulsion. They also play important roles in cell migration, regeneration, neurodegenerative diseases and the development of cancer. Until recently, scientists assumed that ephrin/Eph signal transmission could only occur through direct cell-cell contact. However, Rüdiger Klein and his team at the Max Planck Institute of Neurobiology have now shown that cells can also pack and release active ephrins and Eph receptors through extracellular vesicles. Not only does this discovery improve our understanding of this communication system, it may also pave the way for new therapeutic strategies.

The human body contains up to 100 billion cells. As they grow, migrate, replicate and move, these cells come into contact with countless other cells and exchange information with them. One way this communication happens is through the ephrin/Eph-receptor system, which is able to guide cell migration and the growth of neuronal extensions. In addition, the ephrin-Eph system also plays a role in plastic processes, such as learning and regeneration, as well as in tumour growth and neurodegenerative diseases.

Eph receptors and their binding partners, the ephrins, are found on the surface of almost all cell types. When an ephrin meets the Eph receptor of another cell, they join to form an ephrin-Eph complex. This triggers processes in one or both cells that generally lead to internalization of the complex and repulsion of one cell away from the other. The repelled cell then moves or grows in another direction. In the nervous system, many such interactions guide the extensions of young neurons to their right destinations.

“This is why it’s so fundamentally important to understand how cells use this system to communicate”, says Rüdiger Klein, whose Department at the Max Planck Institute of Neurobiology is studying ephrins and Eph receptors. It had always seemed clear that ephrins and Ephs could only trigger a signaling process by direct contact between two cells. Recently, however, ephrins and Eph receptors have also been found in extracellular vesicles/exosomes – small droplets of fat released by cells, used as transport vehicles, signal transmitters or for eliminating cell components. “This has thrown up the interesting question of what business Ephs and ephrins have in exosomes”, says Klein.

Intrigued, the Martinsried-based team set up an elaborate experimental study to purify the exosomes from different cell types, including neurons, and analyse their contents. They revealed that many of these exosomes contained ephrins and Ephs, and decoded the cellular mechanism by which they were packed into the exosomes. Interestingly, further analysis showed that the Eph receptors had not been dumped as waste products, but remained active on the exosomes. Eph receptors on the exosomes were able to bind to ephrin molecules on the surface of growing neurons and repel the neuronal extensions. This proves, for the first time, that cells can send ephrins and Ephs out to transmit signals over a distance. “It opens up a whole range of new possibilities”, says Rüdiger Klein. Ephrins and Eph receptors have also been found in the exosomes of cancer cells. “This might mean that strategies to control exosome release could be used to interrupt the ephrin-Eph signaling pathway and thereby disrupt tumour growth”, he surmises.

Original Publication:
Jingyi Gong, Roman Körner, Louise Gaitanos, Rüdiger Klein
Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance.
Published June 27, 2016 // JCB vol. 214 no. 1 35-44 The Rockefeller University Press, doi: 10.1083/jcb.201601085

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