jfm1330 wrote: I learned something very surprising today about the sortilin receptor through my readings on the subject, one things leading to another. I must admit that I have been a bit lazy about trying to learn more about sortilin. All that to say that today I spent time searching about it and reading a few articles. It led me to learn a very interisting fact about this transmembrane receptor, the fact that it was possible to cleave the extracellular part of the protein (receptors ore proteins). So the outside part, and hydrophilic part of sortilin can be cleaved by a protease (proteases are enzymes able to break peptide bond, so cut peptides and proteins). So the outside part of sortilin can be released and it becomes a free soluble protein that can flow and go interact with other proteins.
The extracellular domain of the NTSR3/sortilin can be released by its proteinase, and as a result can occur as soluble NT receptor type 3 (sNTSR3), performing biological functions without the involvement of NT. An interesting point is that sNTSR3 or sSORT or soluble sortilin is particularly involved in cancer progression and it can have an effect on cellular morphology and on the adherence between cells.
The mechanisms underlying NTSR3-induced cancer progression depend, in part, on soluble NTSR3 (sNTSR3), which is released by shedding from the extracellular domain of NTSR3; soluble NTSR3 increases intracellular calcium concentrations and induces focal adhesion kinase (FAK)/Src-dependent activation of the inositol1,4,5-trisphosphate (IP3) kinase pathway in adenocarcinoma epithelial cells.21 In addition, sNTSR3 regulates cell morphology, cellcell and cell-matrix adherens properties by decreasing the expression of several integrins and modifying the structure of desmosomes. https://onlinelibrary.wiley.com/doi/pdf/10.1111/1440-1681.12787
So if soluble sortilin can modify desmosomes, making the junction between cells less tight, it can explain in part vasculogenic mimicry. If the cells are not thightly connected, it ressembles what as been described by Thera as vasculogenic mimicry. It could also be implicated in the metastatic process, allowing cancer cells to go free in the bloodstream. Maybe TH1902 interacting with sortilin allows for less sSORT1 to be released, then reducing vasculogenic mimicry process. This is just a guess on my part it is surely more complicated than that. But to think that stimulating the internalization of the sortilin receptor can have an effect on different signaling pathways and their effects is not foolish. By pushing the endocytosis of sortilin, it leaves less of this receptor on the cell membrane, and more inside the cancer cell where it can have an impact on signaling and gene expression. Since we know that the more a cancer is aggressive, the more sortilin there is on the cell membrane, it shows that this is implicated in the aggressivness of the cancer. So reducing sortilin on the membrane, and maybe soluble sortilin can have an effect on the aggressivness of the cancer by messing up the signaling pathways stimulating vasulogenic mimicry and metastasis potential.
A desmosome (;[1][2] "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for adhering spot), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes. Desmosomes are one of the stronger cell-to-cell adhesion types and are found in tissue that experience intense mechanical stress, such as cardiac muscle tissue, bladder tissue, gastrointestinal mucosa, and epithelia.[ https://en.wikipedia.org/wiki/Desmosome
In addition, sNTSR3, shed from the extracellular domain of NTSR3, is responsible for cancer metastasis by inducing the first phase of a process that wakens the desmosome architecture, leading to cell spreading and initiation of cell separation. https://onlinelibrary.wiley.com/doi/pdf/10.1111/1440-1681.12787
In this same article, the is picture describing all kinds of cell signaling involving NTSR receptors, and it shows that sNTSR3 (sSORT1) can be internalized as such by a cancer cell, and once inside the cytoplasm, it can play a role in gene expression signaling cascade. (on page 843, Figure 1)
The article also states what we already knew about overexpression in breast cancer
In addition, immunohistochemistry experiments performed in a cohort of clinical breast cancers and normal breast tissues reveal an increase in the expression of NTSR3 associated with breast cancer aggressiveness, particularly in ductal invasive carcinomas and in association with lymph node invasion. More about the way sSORT can modify cell morphology and tissue structure
In the present study, we sought to examine the role of sNTSR3 on the morphology and behaviour of the colonic epithelial cancer cells HT29. Our data show that sNTSR3 incubation on HT29 cells leads to several changes in cell shape including actin reorganization and cell morphology in relation to a decrease of several integrins. sNTSR3 also induces a strong modification in the architecture of desmosomes. We demonstrate that sNTSR3 induces detachment of several colonic cancer cells including HT29, HCT116 and SW620 cell lines. Taken together, our results demonstrate that the soluble form of NTSR3 may regulate, by a complex mechanism, the fate of the human colonic adenocarcinoma cell line HT29, especially during the initial step of cell detachment.