This Fn3 domain is found towards the C-terminal of human Sortilin-related receptor (SORL1).SORL1 is a multifunctional sorting receptor involved in the intracellular trafficking and localisation of various protein cargoes. It cooperates with the AP-1 complex in Golgi-endosome sorting pathways []and regulates the trafficking of amyloid precursor protein (APP), retaining it in the trans-Golgi network to prevent its processing into amyloidogenic peptides Abeta40 and Abeta42 in late endosomes [, , , ]. It may also facilitate lysosomal degradation of newly formed amyloid-beta peptides []but does not influence APP transport between the endoplasmic reticulum and Golgi compartments []. SORL1 acts as a sorting receptor for several other key proteins, including the BDNF receptor NTRK2/TRKB, promoting its intracellular redistribution and enhancing BDNF signalling []; GDNF and its receptor GFRA1, directing GDNF for lysosomal degradation while recycling GFRA1 and mediating RETendocytosis [, ]; ERBB2/HER2, regulating its recycling to the plasma membrane to sustain PI3K-dependent signalling and support proliferation in ERBB2-driven cancers []; lipoprotein lipase (LPL), targeting it for lysosomal degradation []; APOA5, inducing its internalisation and sorting to both lysosomes and the trans-Golgi network []; and the insulin receptor (INSR), promoting its recycling to the cell surface and enhancing insulin responsiveness in adipose tissue without affecting its internalisation []. SORL1 also plays roles in renal ion homeostasis through the intracellular sorting of STK39 and PPP3CB, and its N-terminal ectodomain promotes proliferation and migration of smooth muscle cells via uPAR/PLAUR, contributing to extracellular matrix remodelling and intimal thickening following vascular injury []. It further supports monocyte adhesion []and may enhance monocyte/macrophage proliferation and migration, contributing to foam cell formation and atherosclerosis. In haematopoietic stem and progenitor cells, SORL1 mediates hypoxia-enhanced adhesion to bone marrow stroma via PLAUR []. Additionally, it functions as a metabolic regulator that limits adipose tissue energy expenditure by inhibiting the BMP/Smad pathway, and may modulate signalling of the CLCF1-CRLF1-CNTFR complex and IL6 by promoting lysosomal degradation and shifting the balance between cis and trans IL6 signalling [, ].
