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. 2016 Jan 11;9(1):e1130192.
doi: 10.1080/19420889.2015.1130192. eCollection 2016 Jan-Feb.

A new role under sortilin's belt in cancer

Cornelia M Wilson  1 , Thomas Naves  2 , Hussein Al Akhrass  2 , François Vincent  3 , Boris Melloni  4 , François Bonnaud  4 , Fabrice Lalloué  2 , Marie-Odile Jauberteau  2
Affiliations

A new role under sortilin's belt in cancer

Cornelia M Wilson et al. Commun Integr Biol. .

Abstract

The neurotensin receptor-3 also known as sortilin was the first member of the small family of vacuolar protein sorting 10 protein domain (Vps10p) discovered two decades ago in the human brain. The expression of sortilin is not confined to the nervous system but sortilin is ubiquitously expressed in many tissues. Sortilin has multiple roles in the cell as a receptor or a co-receptor, in protein transport of many interacting partners to the plasma membrane, to the endocytic pathway and to the lysosomes for protein degradation. Sortilin could be considered as the cells own shuttle system. In many human diseases including neurological diseases and cancer, sortilin expression has been shown to be deregulated. In addition, some studies have highlighted that the extracellular domain of sortilin is shedded into the culture media by an unknown mechanism. Sortilin can be released in exosomes and appears to control some mechanisms of exosome biogenesis. In lung cancer cells, sortilin can associate with two receptor tyrosine kinase receptors called the TES complex found in exosomes. Exosomes carrying the TES complex can convey a microenvironment control through the activation of ErbB signaling pathways and the release of angiogenic factors. Deregulation of sortilin function is now emerging to be implicated in four major human diseases- cardiovascular disease, Type 2 diabetes mellitus, Alzheimer disease and cancer.

Keywords: EGFR; TrkB; exosome; lung cancer; sortilin.

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Figures

Figure 1.
Figure 1.
Main discoveries in extracellular vesicle biology. Timeline showing the main discoveries in the extracellular vesicle research.
Figure 2.
Figure 2.
Role of sortilin in EV biogenesis. Sortilin is initially synthesized in the constitutive secretory pathway as a precursor encoding a short propeptide sequence. The propeptide is cleaved by pro-protein convertases at the TGN allowing sortilin to enter the secretory pathway (stage 1). There are a number of likely routes that sortilin can be trafficked. Sortilin can be trafficked along a number of possible routes such as trafficking to the plasma membrane through constitutive secretory vesicles (stage 2). Alternatively, sortilin could be anterograde transported from the TGN by itself or with its binding partners to the early endosomes (stage 3). Sortilin present at the cell surface or in the endocytic pathway could be cleaved by disintegrin and metalloproteinase domain-converting protein (ADAM) 10 or ADAM17, and followed by g-secretase (stage 5). Following endoproteolytic cleavage, sortilin could form a heterotrimeric complex with TrkB and EGFR (TES complex) which is internalized through a clathrin-dependent endocytosis process into early endosomes (stage 6). At the plasma membrane, the purple spots represent clathrin associated with vesicles (clathrin-coated vesicles [CCV]) or the bilayered clathrin coats at the endosome. The intraluminal vesicles (ILV) are formed by an invagination event at the membrane of the late endosomes/multivesicular body (MVB). Sortilin may play a role in the recruitment of certain cargo such as its binding partners- TrkB and EGFR, which could be an ESCRT-dependent mechanism. The MVB and its content could be degraded via the lysosome-mediated pathway for degradation or alternatively the MVB are transported to the cell surface were they dock at the plasma membrane requiring Rab27A to release the vesicles into the extracellular space (stage 7). The exosomes carrying the TES complex could be released and taken up in the target cell. The uptake of TES-containing exosomes initiates cellular communication through upregulation of cell signaling events by the induction of cell survival through the EGFR cascade and the angiogenesis process (stage 8).
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