Reverse Signalling


Cellular signal transduction is defined as the conversion of an extracellular signal to a response within a cell. Commonly referred to as forward signalling, this extracellular signal often comes in the form of a soluble ligand that binds to a membrane‐spanning receptor. However, many ligands or their precursors are also transmembrane or membrane associated. It is now appreciated that these ligands may also act as receptors in a process referred to as reverse signalling. There is a growing body of evidence that reverse signalling occurs for several classes of ligands including: ephrins, semaphorins, interleukins, tumour necrosis factor family members and Notch‐associated ligands. This type of signalling has been linked to immune responses, axon guidance, cell proliferation and differentiation. Here we review reverse signalling of ligands categorised by how they associate with the membrane: transmembrane type 1 (TM1), transmembrane type 2 (TM2), or GPI‐linked. Within this structure we will emphasize the physiological and pathological roles of reverse signaling.

Key Concepts

  • Ligand classes that possess the ability to reverse signal include, but are not limited to, members of the tumour necrosis factor superfamily (TNFSF), ephrin family, semaphorin family, interleukin family and Notch‐associated ligands.
  • These ligands can be categorized into the following subgroups: transmembrane type 1 (TM1), transmembrane type 2 (TM2), and GPI‐linked.
  • Ligands can reverse signal by directly recruiting adaptor or effector proteins, acting in concert with coreceptors or by liberation of the intracellular domain to influence transcription.
  • Reverse signalling has been shown to be involved in processes including axon guidance, tissue development and immune responses.
  • Ectopic regulation of reverse signalling is associated with a range of pathologies including cancer, developmental defects and osteoporosis.

Keywords: signal transduction; reverse signalling; bidirectional signalling; ephrin; semaphorin; tumour necrosis factor superfamily (TNFSF); axon guidance

Figure 1. Ligands capable of reverse signalling. A small number of ligands and their downstream reverse signalling pathways and cellular functions have been well characterised. Among these are TM1 ligands (EphrinB, Sema1A, Sema6D, tmIL‐15, DeltaD, Jagged1 and NRG1), TM2 ligands (mTNFα, FasL) and GPI‐linked ligands (Ephrin A). These ligands are involved in a number of cellular functions ranging from axonal regulation to cell proliferation and migration. A large number of these ligands reverse signal through intracellular domains that contain CK1 phosphorylation sites, PDZ‐binding or proline‐rich domains, capable of recruiting adaptor/effector proteins. Other ligands lack these intracellular domains and signal through alternative methods (e.g. recruitment of coreceptors or cleavage).


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Further Reading

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Ross, Emily F, Ali, Maria F, Woo, Laura A, Chadwick, Sean R, Lee, Eunji, Sangston, Ryan M, Sood, Chhavi, Zhang, Qi, Zhang, Xiaomu, and Deppmann, Christopher D(Sep 2016) Reverse Signalling. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026897]