Sortilin (human) (rec.) (His)

Sortilin is a type I transmembrane multiligand receptor that is a member of the Vacuolar protein sorting 10 protein (Vps10p) domain receptor family. It is a 95 kDa protein, ubiquitously expressed, although most abundantly expressed in neurons, hepatocytes, adipocytes and white blood cells including macrophages. Sortilin is synthesized as a propeptide in the endoplasmic reticulum (ER) and processed to its mature form by furin-mediated cleavage in the trans-Golgi network.

The primary function of sortilin is trafficking proteins from the Golgi to secretory vesicles and endolysosomal compartments. The majority of trafficking is from the Golgi to the endosomal compartment where sortilin deposits cargo targeted for catabolism in the lysosome and then is trafficked back to the Golgi via a retromer complex. At the cell surface, sortilin can remain intact and act as a receptor for extracellular ligands that can initiate signaling cascades or be internalized as a method of receptor-mediated endocytosis. Additionally, cell surface sortilin protein can undergo an additional cleavage that results in the release of the soluble form of the protein into the extracellular space.

The sortilin receptor binds the nerve growth factor precursor (proNGF), neurotensin and Progranulin (PGRN), a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing, tumorigenesis and neurological diseases. Sortilin controls PGRN trafficking (endocytosis) and is indirectly involved in lysosomal degradation of PGRN. Sortilin down-regulation via blocking antibodies is a key mechanism in increasing extracellular PGRN levels suggesting that sortilin is a potential target to correct PGRN reduction, such as that in patients with frontotemporal dementia (FTD) caused by GRN mutations.