Summary
Specificity
Human, Rat, Mouse
Basic Information
Immunogen
Human LR11 aa 1220-1337.
Specificity
Human, Rat, Mouse
Application Notes
The COA includes recommended starting dilutions, optimal dilutions should be determined by the end user.
Formulations & Storage [For reference only, actual COA shall prevail!]
Storage
Store at 4°C short term (1-2 weeks). Aliquot and store at -20°C long term. Avoid repeated freeze/thaw cycles.
Target
Full Name
Sortilin Related Receptor 1
Introduction
SORL1 is a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. SORL1 also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely functions in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease.
Alternative Names
Sortilin Related Receptor 1; LDLR Relative With 11 Ligand-Binding Repeats; Low-Density Lipoprotein Receptor Relative With 11 Ligand-Binding Repeats; Sorting Protein-Related Receptor Containing LDLR Class A Repeats; C11orf32; SorLA-1; SORLA; LR11
Function
Sorting receptor that directs several proteins to their correct location within the cell (Probable). Along with AP-1 complex, involved Golgi apparatus - endosome sorting (PubMed:17646382).
Sorting receptor for APP, regulating its intracellular trafficking and processing into amyloidogenic-beta peptides. Retains APP in the trans-Golgi network, hence preventing its transit through late endosomes where amyloid beta peptides Abeta40 and Abeta42 are generated (PubMed:16174740, PubMed:16407538, PubMed:17855360, PubMed:24523320).
May also sort newly produced amyloid-beta peptides to lysosomes for catabolism (PubMed:24523320).
Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments (PubMed:17855360).
Sorting receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling by controlling the intracellular location of its receptor (PubMed:23977241).
Sorting receptor for GDNF that promotes GDNF regulated, but not constitutive secretion (PubMed:21994944).
Sorting receptor for the GDNF-GFRA1 complex, directing it from the cell surface to endosomes. GDNF is then targeted to lysosomes and degraded, while its receptor GFRA1 recycles back to the cell membrane, resulting in a GDNF clearance pathway. The SORL1-GFRA1 complex further targets RET for endocytosis, but not for degradation, affecting GDNF-induced neurotrophic activities (PubMed:23333276).
Sorting receptor for ERBB2/HER2. Regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. In ERBB2-dependent cancer cells, promotes cell proliferation (PubMed:31138794).
Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL (PubMed:21385844).
Potential sorting receptor for APOA5, inducing APOA5 internalization to early endosomes, then to late endosomes, wherefrom a portion is sent to lysosomes and degradation, another portion is sorted to the trans-Golgi network (PubMed:18603531).
Sorting receptor for the insulin receptor INSR. Promotes recycling of internalized INSR via the Golgi apparatus back to the cell surface, thereby preventing lysosomal INSR catabolism, increasing INSR cell surface expression and strengthening insulin signal reception in adipose tissue. Does not affect INSR internalization (PubMed:27322061).
Plays a role in renal ion homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly through intracellular sorting of STK39 and PPP3CB (By similarity).
Stimulates, via the N-terminal ectodomain, the proliferation and migration of smooth muscle cells, possibly by increasing cell surface expression of the urokinase receptor uPAR/PLAUR. This may promote extracellular matrix proteolysis and hence facilitate cell migration (PubMed:14764453).
By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury (PubMed:14764453).
Promotes adhesion of monocytes (PubMed:23486467).
Stimulates proliferation and migration of monocytes/macrophages (By similarity).
Through its action on intimal smooth muscle cells and macrophages, may accelerate intimal thickening and macrophage foam cell formation in the process of atherosclerosis (By similarity).
Regulates hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to the bone marrow stromal cells via a PLAUR-mediated pathway. This function is mediated by the N-terminal ectodomain (PubMed:23486467).
Metabolic regulator, which functions to maintain the adequate balance between lipid storage and oxidation in response to changing environmental conditions, such as temperature and diet. The N-terminal ectodomain negatively regulates adipose tissue energy expenditure, acting through the inhibition the BMP/Smad pathway (By similarity).
May regulate signaling by the heterodimeric neurotrophic cytokine CLCF1-CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation (PubMed:26858303).
May regulate IL6 signaling, decreasing cis signaling, possibly by interfering with IL6-binding to membrane-bound IL6R, while up-regulating trans signaling via soluble IL6R (PubMed:28265003).
Biological Process
Biological Process adaptive thermogenesisISS:UniProtKB
Biological Process cell migrationIEA:Ensembl
Biological Process cell population proliferationIEA:Ensembl
Biological Process diet induced thermogenesisISS:UniProtKB
Biological Process insulin receptor recyclingManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of amyloid-beta formationManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process negative regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic processManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process negative regulation of BMP signaling pathwayISS:UniProtKB
Biological Process negative regulation of MAP kinase activityISS:Alzheimers_University_of_Toronto
Biological Process negative regulation of metalloendopeptidase activity involved in amyloid precursor protein catabolic processManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process negative regulation of neurofibrillary tangle assemblyISS:Alzheimers_University_of_Toronto
Biological Process negative regulation of neurogenesisISS:Alzheimers_University_of_Toronto
Biological Process negative regulation of neuron deathISS:Alzheimers_University_of_Toronto
Biological Process negative regulation of protein bindingManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process negative regulation of protein-containing complex assemblyManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process negative regulation of tau-protein kinase activityISS:Alzheimers_University_of_Toronto
Biological Process negative regulation of triglyceride catabolic processISS:UniProtKB
Biological Process neuropeptide signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of adipose tissue developmentManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of choline O-acetyltransferase activityISS:Alzheimers_University_of_Toronto
Biological Process positive regulation of early endosome to recycling endosome transportManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process positive regulation of endocytic recyclingManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process positive regulation of ER to Golgi vesicle-mediated transportManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process positive regulation of glial cell-derived neurotrophic factor productionManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of insulin receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of protein catabolic processManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process positive regulation of protein exit from endoplasmic reticulumManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process positive regulation of protein localization to early endosomeManual Assertion Based On ExperimentIMP:Alzheimers_University_of_Toronto
Biological Process post-Golgi vesicle-mediated transportManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process protein localization to Golgi apparatusManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process protein maturationManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process protein retention in Golgi apparatusManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process protein targetingManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process protein targeting to lysosomeManual Assertion Based On ExperimentIDA:Alzheimers_University_of_Toronto
Biological Process receptor-mediated endocytosisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of smooth muscle cell migrationManual Assertion Based On ExperimentIDA:UniProtKB
Cellular Location
Golgi apparatus membrane
Golgi apparatus, trans-Golgi network membrane
Endosome membrane
Early endosome membrane
Recycling endosome membrane
Endoplasmic reticulum membrane
Endosome, multivesicular body membrane
Cell membrane
Cytoplasmic vesicle, secretory vesicle membrane
Secreted
Mostly intracellular, predominantly in the trans-Golgi network (TGN) and in endosome, as well as in endosome-to-TGN retrograde vesicles; found at low levels on the plasma membrane (PubMed:11294867, PubMed:15053742, PubMed:17855360, PubMed:21994944, PubMed:21385844, PubMed:31138794).
At the cell surface, partially subjected to proteolytic shedding that releases the ectodomain (also called soluble SORLA, solLR11 or sLR11) in the extracellular milieu (PubMed:11082041, PubMed:16393139, PubMed:16531402).
The shedding may be catalyzed by ADAM17/TACE (PubMed:16393139).
Following shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane fragment and catalyzes the release of a C-terminal fragment in the cytosol and of a soluble N-terminal beta fragment in the extracellular milieu. The C-terminal cytosolic fragment localizes to the nucleus (PubMed:16531402).
At the cell surface, the full-length protein undergoes partial clathrin-dependent endocytosis guided by clathrin adapter protein 2 (AP-2) (PubMed:11294867, PubMed:15053742, PubMed:17646382).
Involvement in disease
Alzheimer disease (AD):
Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
Topology
Lumenal: 82-2137
Helical: 2138-2158
Cytoplasmic: 2159-2214
PTM
Within the Golgi apparatus, the propeptide may be cleaved off by FURIN or a furin-like protease (Probable). After cleavage, the propeptide interacts with the mature protein N-terminus, preventing the association with other ligands (PubMed:11294867).
At the cell surface, partially subjected to proteolytic shedding that releases the ectodomain in the extracellular milieu (PubMed:11082041, PubMed:16393139, PubMed:16531402, PubMed:28265003).
The shedding may be catalyzed by ADAM17/TACE (PubMed:16393139, PubMed:16531402).
Following shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane fragment and catalyzes the release of a C-terminal fragment in the cytosol and of a soluble N-terminal beta fragment in the extracellular milieu. The C-terminal cytosolic fragment localizes to the nucleus (PubMed:16531402).
Phosphorylation at Ser-2206 facilitates the interaction with GGA1.