Sortilin-related receptor - P0DSP1 (SORL_RAT)


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Sorting receptor that directs several proteins to their correct location within the cell. Along with AP-1 complex, involved Golgi apparatus - endosome sorting. 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. May also sort newly produced amyloid-beta peptides to lysosomes for catabolism. Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments. 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 (By similarity). 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 (By similarity). Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL. 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. 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 (By similarity). 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 (PubMed:25967121). 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. By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury (By similarity). Stimulates proliferation and migration monocytes/macrophages. 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 (By similarity). 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. Might regulate IL6 signaling, decreasing cis signaling, while up-regulating trans signaling (By similarity). UniProt
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Subunit Structure
After maturation cleavage, interacts (via N-terminus) with its own propeptide; this interaction prevents interaction with other ligands, including CRLF1, GDNF, GFRA1, IL6 and IL6R. Interacts (via N-terminal ectodomain) with APP, forming a 1:1 stoichiometric complex, including with isoforms APP695, APP751 and APP770. Also interacts with APP C-terminal fragment C99 and with Abeta40. Interacts with beta-secretase BACE1/BACE; this interaction may affect BACE1-binding to APP and hence reduce BACE1-dependent APP cleavage. Interacts with LRPAP1/RAP. Interacts (via C-terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS domain). Interacts with PACS1. May interact (via the N-terminal ectodomain) with the morphogenetic neuropeptide, also called head activator or HA; this interaction is impaired in the presence of propeptide. Interacts with neurotensin/NTS. Interacts (via the N-terminal ectodomain) with PDGFB homodimer. Interacts (via N-terminal ectodomain) with the uPA receptor PLAUR. Interacts with uPA/PLAU and PAI1/SERPINE1, either individually or in complex with each other, leading to endocytosis. Also interacts with PAI1/SERPINE1 in complex with tPA/PLAT. Interacts (via C-terminus) with AP-1 and AP-2 complexes (By similarity). Interacts with BMPR1A and BMPR1B (By similarity). Interacts with lipoprotein lipase LPL; this interaction is optimal in slightly acidic conditions (By similarity). Interacts (via N-terminal ectodomain) with GDNF (via propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in complex with each other (PubMed:21994944, PubMed:23333276). Also interacts with other GDNF receptor alpha family members, including GFRA2, GFRA3 and GFRA4. Interacts with the insulin receptor INSR; this interaction strongly increases the surface exposure of INSR. Interacts (via cytosolic C-terminus) with STK39/SPAK. Interacts (via N-terminal ectodomain) with the heterodimeric complex CRLF1-CLC; within this complex, the interaction is mediated predominantly by the CRLF1 moiety. Interacts with CNTFR, as well as with the tripartite signaling complex formed by CRLF1, CLC and CNTFR. Interacts (via N-terminal ectodomain) with IL6; this interaction leads to IL6 internalization and lysosomal degradation. Binding of SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans signaling. Interacts with secreted IL6R; this interaction leads to IL6R internalization. Also interacts with transmembrane IL6R; this interaction does not seem to affect subcellular location. Interacts with APOE (By similarity). Interacts with apolipoprotein E-rich beta-VLDL (By similarity). Interacts with APOA5; this interaction leads to APOA5 internalization and is abolished by heparin. Interaction with APOA5 results in enhanced binding to chylomicrons. Interacts with ROCK2 (By similarity). Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta (PubMed:25967121). Interacts with NTRK2/TRKB (By similarity). Interacts (via cytosolic C-terminus) with HSPA12A in an ADP-dependent manner; this interaction affects SORL1 internalization and subcellular localization (By similarity). Interacts (via N-terminal ectodomain) with ERBB2/HER2 (By similarity). UniProt
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