Sortilin mediates the release and transfer of exosomes in concert with two tyrosine kinase receptors

Abstract

The transfer of exosomes containing both genetic and protein materials is necessary for the control of the cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, and the mechanism of their action in membrane transport and related signaling events are not clearly understood. In this study, we demonstrate, in human lung cancer A549 cells, that the exosome release mechanism is closely linked to the multifaceted receptor sortilin (also called neurotensin receptor 3). Sortilin is already known to be important for cancer cell function. Here, we report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This new complex (termed the TES complex) is found in exosomes and results in the linkage of the two tyrosine kinase receptors TrkB (also known as NTRK2) and EGFR with sortilin. Using in vitro models, we demonstrate that this sortilin-containing complex exhibits a control on endothelial cells and angiogenesis activation through exosome transfer.

Challenges and Strategies in Precision Medicine for Non-Small-Cell Lung Cancer

“…Microenvironment communication through neurotrophin signalling could lead to the progression of cancer [157][158][159] while an imbalance in expression of neurotrophin receptors such as sortilin is strongly linked to different types of cancer [160][161][162][163]. In a previous study, we discovered that the EGFR signalling pathways are induced between 3 to 50-fold in endothelial cells exposed to NSCLC exosomes enriched for the neurotensin receptor 3, also known as sortilin [125].…”

“…Exosomes (ranging in size 30 to 100 nm) are the smallest class of EVs found in most body fluids, are derived by an inward budding event of the late endosome or multivesicular body [122,123]. Exosomes contain a plethora of signalling proteins, miRNA, mRNA and lipids [124,125]. They are released from both healthy and cancer cells but their numbers increase exponentially with progression of cancer.…”

“…In fact, it's necessary to analyse the whole population of EVs to be certain not to exclude certain populations. The sizes of vesicles can be altered through modification of the lipid content and the exosome formation processes occurring at the multivesicular body [125]. In patients with lung adenocarcinoma, circulating exosomes were significantly higher than in control group [83].…”

“…In a recent study, NSCLC patients were distinguished from control subjects via differential display of 30 EV protein biomarkers from plasma using an ELISA-based method [169]. We have reported that a specific marker of NSCLC exosomes, sortilin forms a trimeric complex with two tyrosine kinase receptors TrkB (also known as NTRK2) and EGFR called the TES complex [125]. Altogether, these data indicate the need to identify specific biomarkers and to develop specific EV technology for lung cancer.…”

Exosomes: nanoshuttles to the future of BioMedicine

“…3 This Exosomal Cargo Selecting and Transporting Apparatus (ECSTA) could comprise the following components or their functional analogs: (i) proteins from ESCRT (Endosomal Sorting Complex Required for Transport) and others functionally associated, as Alix and TSC101; 4 (ii) Rab family members and other proteins involved in membrane trafficking, as GAPs and GEFs; 5 (iii) sortilin and functionally associated proteins, as TrkB and EGFR; 6 (iv) exosomal RNA-binding proteins (RBPs); 4 (v) miRNAs, long non-coding RNAs (lncRNAs), competing endogenous RNAs (ceRNAs), and other ncRNAs, 7 regulating synthesis, expression and activity of ECSTA protein members. Our data highlight questions that deserve to be experimentally explored.…”