The new fate of internalized membrane receptors: Internalized activation

https://doi.org/10.1016/j.pharmthera.2021.108018Get rights and content

Abstract

Classically, the fate of internalized membrane receptors includes receptor degradation and receptor recycling. However, recent findings have begun to challenge these views. Much research demonstrated that many internalized membrane receptors can trigger distinct signal activation rather than being desensitized inside the cell. Here, we introduce the concept of “internalized activation” which not only represents a new mode of receptor activation, but also endows the new fate for receptor internalization (from death to life). The new activation mode and fate of membrane receptor are ubiquitous and have unique theoretical significance. We systematically put forward the features, process, and regulation of “internalized activation” and its significance in signal transduction and diseases. “Internalized activation” will provide a completely new understanding for the theory of receptor activation, internalization and novel drug targets for precision medicine.

Introduction

Plasma membrane receptors are the most important membrane proteins that involved in almost all physiological and pathological processes. Dysfunction of receptors is an important mechanism for major diseases including cardiovascular diseases, tumors, metabolic diseases and neurodegenerative diseases. Therefore, it is not surprising that more than 50% of clinical drug targets are receptors (Hauser, Attwood, Rask-Andersen, Schiöth, & Gloriam, 2017). Traditionally, membrane receptor internalization has been considered to lead to receptor desensitization and signaling termination. However, the recent advance in technologies, such as single-molecule imaging, live cell total internal reflection fluorescence (TIRF), nanobodies, and signal molecule probes, enables us to more deeply understand the spatiotemporal behaviors of the receptor internalization (Irannejad et al., 2013; Lohse, Nuber, & Hoffmann, 2012). Research continues to show that the receptor internalization can also lead to signal activation in certain conditions (Civciristov et al., 2019; Di Guglielmo, Baass, Ou, Posner, & Bergeron, 1994; Irannejad et al., 2013; Nguyen et al., 2019; Parsons & May, 2019; Vieira, Lamaze, & Schmid, 1996). The phenomenon of the receptor internalization-dependent activation is widely observed in almost all kinds of receptors, including G protein-coupled receptor (GPCR), receptor tyrosine kinase (RTK), transforming growth factor-β receptor (TGFβR), Notch, tumour-necrosis factor receptor (TNFR), Toll-like receptor (TLR), et al. (Stasyk & Huber, 2016) (Table 1). A wide range of signaling pathways are also found to be activated by internalized receptors, including MAPK pathway, AKT pathway, Smad pathway, Notch pathway, Wnt pathway, et al. (Flinn, Yan, Goswami, Parker, & Backer, 2010; von Zastrow & Sorkin, 2007). These receptor internalization-mediated signals functionally regulate diverse phenotypic outputs, including metabolism, cancer, neurodegeneration, immune regulation, and others. The “internalized activation” that the receptor internalization leads to receptor signaling activation not only has universality, but also has uniqueness (Wang, Bian, & Li, 2021). This new mode of receptor activation is completely different from both classical membrane activation and internalization-independent intracellular activation (Fig. 1).

Internalized activation, as a new mode of receptor activation, expands the understanding of the fates of receptor internalization. The traditional fates of the receptor internalization include receptor recycling and receptor degradation. However, “internalized activation” endows the third fate for receptor internalization (Fig. 2). The new fate of internalized membrane receptors, internalized activation, will provide a completely new understanding for the theory of membrane receptor internalization and novel drug targets for precision medicine.

Section snippets

New insights into internalization of membrane receptors

Internalized activation provides new insights into internalization of membrane receptors, including the internalization fate of receptors, the role of receptors and the diversity for a single receptor.

The initiation of internalized activation

Internalized activation is a precise integration system. The process mainly includes: initiation, internalization and signaling activation. The initiation system of internalized activation mainly includes ligands and receptors.

The internalization routes of internalized activation

Internalization is the key process and a fundamental feature for the internalized activation. Here, we summarize the major routes of internalized activation and how these routes precisely control the outcomes of internalized activation.

The signaling location of internalized activation

In internalized activation, the trafficking receptor can trigger signaling activation at different locations, including endocytosis vesicles, organelles and nucleus (Fig. 5).

Internalized activation can happen in endocytosis vesicles. Clathrin coated-pit is the most reported endocytosis vesicle for internalized activation. For example, class A GPCR such as β-AR could be internalized to clathrin-coated pits and trigger ERK1/2 activation (Eichel, Jullié, & von Zastrow, 2016). Internalized

The regulation of internalized activation

Internalized activation can be regulated at different levels, including receptor, scaffolding protein, and organelle regulation. These regulatory mechanisms make the receptor internalized activation more precise.

Internalized activation and diseases

“Internalized activation” brings us a brand-new understanding of diseases. The pathogenesis of many diseases can be traced back to abnormalities of internalized activation. Essentially all stations of internalized activation, from receptor agonism, internalization initiation and receptor trafficking, to signaling location, can affect the occurrence and development of diseases. Here, we take RTK as an example to systematically clarify how the process of internalized activation affects diseases.

Conclusion and future directions

The breakthrough of technology has always been the key to the development of scientific theory. In recent years, some advanced and unique technologies have made great progress in the study of precise membrane receptor behaviors and functions. These unique technologies include live cell TIRF microscopy, nanobodies and subcellular signal detection method, etc. These advanced technologies revealed the phenomena of receptor internalization-mediated signaling activation in different types of

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors acknowledge funding support from the National Natural Science Foundation of China (91939301, 81820108031, 91539123, 81471893), Beijing Municipal Natural Science Foundation (7172235), and Medical research management/basic and clinical research unit of metabolic cardiovascular diseases, Chinese Academy of Medical Sciences (2021RU003).

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    Wenjing Wang and Jingwei Bian are co-first authors. Both contributed equally to this article.

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