Transmembrane chemokines act as receptors in a novel mechanism termed inverse signaling
Kirsten Hattermann Henrike Gebhardt Sebastian Krossa Andreas Ludwig Ralph Lucius Janka Held-Feindt Rolf Mentlein
University of Kiel, Germany; Institute of Zoology, Germany; RWTH Aachen University, Germany; University Medical Center Schleswig-Holstein, Germany
Published January 21, 2016
Cite as eLife 2016;5:e10820
The transmembrane chemokines CX3CL1/fractalkine and CXCL16 are widely expressed in different types of tumors, often without an appropriate expression of their classical receptors. We observed that receptor-negative cancer cells could be stimulated by the soluble chemokines. Searching for alternative receptors we detected that all cells expressing or transfected with transmembrane chemokine ligands bound the soluble chemokines with high affinity and responded by phosphorylation of intracellular kinases, enhanced proliferation and anti-apoptosis. This activity requires the intracellular domain and apparently the dimerization of the transmembrane chemokine ligand. Thus, shed soluble chemokines can generate auto- or paracrine signals by binding and activating their transmembrane forms. We term this novel mechanism “inverse signaling”. We suppose that inverse signaling is an autocrine feedback and fine-tuning system in the communication between cells that in tumors supports stabilization and proliferation.
The cells that make up an animal need to communicate with each other for a variety of purposes, including controlling the growth and repair of tissues. Commonly, such signaling involves ‘ligand’ molecules binding to specific ‘receptor’ proteins embedded in the cell membrane. When a ligand docks to the right receptor protein, the parts of the receptor inside the cell change shape. This activates signaling pathways within that cell.
Types of ligands called transmembrane ligands are found embedded in cell membranes. Some cancer cells have high levels of transmembrane ligands called CXCL16 and CX3CL1 but do not produce the corresponding receptors for these molecules. The part of these ligands that sits outside of the cells can also be separated from the rest of the molecule to produce a soluble ligand that can move around outside the cell.
By studying cancer cells using microscopy and biochemical approaches, Hattermann, Gebhardt et al. now show that the soluble forms of CXCL16 and CX3CL1 bind to their transmembrane equivalents. This activates signaling pathways that promote cell growth and make the cancer cells more resistant to cell death. However, this signaling did not occur if the transmembrane ligands were altered to lack the part normally found inside the cell, which suggests that transmembrane CXCL16 and CX3CL1 act as receptors.
It was not previously known that a soluble ligand could activate its transmembrane equivalent. Hattermann, Gebhardt et al. have named this process “inverse signaling”, and suggest that it helps to fine-tune the communication between cells. Future experiments will need to study the importance of inverse signaling in living animals and investigate how it works alongside other signaling methods.
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