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EPS15 and epsins act at the initial steps of internalization, serving to recruit the enzymes required for ubiquitination of downstream components of the endocytic pathway. For the EGF receptor, for example, these are EPS15, epsin and ESCRTs (endosomal sorting complexes required for transport), which contain one or more ubiquitin-binding domains (UBDs).

Subsequent delivery of membrane receptors to the lysosome requires accurate recognition of the ubiquitinated cargo by endosomal adaptors and sorting proteins. Ubiquitination of the receptor provides the crucial signal for entering this pathway. Receptors that are internalized after activation are directed first into the endosomes of the endocytic pathway, and then into multivesicular bodies (MVBs), which undergo a process of maturation that ends with fusion with the lysosome and delivery of the contents for degradation.

This device controls a vast array of mammalian signaling receptors, such as receptor tyrosine kinases, G-protein coupled receptors (GPCRs), growth hormone receptors, the major histocompatibility complex I, NOTCH, various channels and transporters, and cytokine and interferon receptors. The covalent attachment of one, or often more, ubiquitin moieties has emerged as the principal mechanism for termination of signaling, by targeting the receptor for endocytosis and, ultimately, degradation in the lysosome. Signal transduction from transmembrane cell surface receptors to nuclear transcription factors is regulated at multiple levels by protein ubiquitination.

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