Endosomes: a legitimate platform for the signaling train

Abstract

Although long regarded as a conduit for the degradation or recycling of cell surface receptors, the endosomal system is also an essential site of signal transduction. Activated receptors accumulate in endosomes, and certain signaling components are exclusively localized to endosomes. Receptors can continue to transmit signals from endosomes that are different from those that arise from the plasma membrane, resulting in distinct physiological responses. Endosomal signaling is widespread in metazoans and plants, where it transmits signals for diverse receptor families that regulate essential processes including growth, differentiation and survival. Receptor signaling at endosomal membranes is tightly regulated by mechanisms that control agonist availability, receptor coupling to signaling machinery, and the subcellular localization of signaling components. Drugs that target mechanisms that initiate and terminate receptor signaling at the plasma membrane are widespread and effective treatments for disease. Selective disruption of receptor signaling in endosomes, which can be accomplished by targeting endosomal-specific signaling pathways or by selective delivery of drugs to the endosomal network, may provide novel therapies for disease.

Fig. 1.

Signaling endosomes transport NGF signals from axon terminals to the cell body of neurons, resulting in activation of ERK5 in the cell body and neuronal survival. In contrast, TrkA activated directly at the cell body activates both ERK5 and ERK1/2. P, phosphate.

Fig. 2.

βarrs recruit signaling complexes to endosomes. Complexes can include activators and inhibitors of signaling. Overlapping symbols specify direct interaction with βarr.

Fig. 3.

Endosomes are key to TLR signaling. The figure depicts the requirement of TLR4 internalization to endosomes for the exchange of the TIRAP-MyD88 signaling complex with the TRAM–TRIF signaling complex.

Fig. 4.

Endosomal ECE-1 regulates SP-induced ERK activation and cell death. (1) SP binding to the NK₁R leads to recruitment of βarr to the receptor, assembly of a MAPK signalosome, and ERK1/2 activation. (2) Degradation of SP by ECE-1 in acidified endosomes disrupts the SP/NK₁R/βarr/MAPK signalosome. (3) NK₁R recycles to the plasma membrane for resensitization. (4) Inhibiting ECE-1 activity causes sustained ERK1/2 activation and SP-induced cell death.