The heterodimer formed by NGFR and SORCS2 functions as receptor for the precursor forms of NGF (proNGF) and BDNF (proBDNF) (PubMed:22155786, PubMed:24908487, PubMed:27457814, PubMed:29909994). ProNGF and proBDNF binding both promote axon growth cone collapse (in vitro) (PubMed:24908487). Plays a role in the regulation of dendritic spine density in hippocampus neurons (PubMed:29909994). Required for normal neurite branching and extension in response to BDNF (PubMed:27457814, PubMed:29909994). Plays a role in BDNF-dependent hippocampal synaptic plasticity (PubMed:29909994, PubMed:27457814). Together with NGFR and NTRK2, is required both for BDNF-mediated synaptic long-term depression and long-term potentiation (PubMed:27457814). ProNGF binding promotes dissociation of TRIO from the heterodimer, which leads to inactivation of RAC1 and/or RAC2 and subsequent reorganization of the actin cytoskeleton (By similarity). Together with the retromer complex subunit VPS35, required for normal expression of GRIN2A at synapses and dendritic cell membranes (PubMed:28469074). Required for normal expression of the amino acid transporter SLC1A1 at the cell membrane, and thereby contributes to protect cells against oxidative stress (PubMed:30840898). Homodimer (in vitro) (PubMed:30061605). Heterodimer with NGFR (PubMed:22155786, PubMed:24908487, PubMed:27457814). The extracellular domains of the heterodimer bind the precursor form of NGF (proNGF) (PubMed:22155786). Can also bind mature NGF and BDNF. Each chain in the receptor dimer interacts (via extracellular domain) with an NGF dimer (in vitro) (PubMed:30061605). Interacts with the precursor forms of BDNF (proBDNF) and NTF3 (proNT3) (By similarity). The cytoplasmic region of the heterodimer formed by NGFR and SORCS2 binds TRIO. ProNGF binding mediates dissociation of TRIO from the receptor complex (By similarity). Interacts with SLC1A1 (PubMed:30840898). Interacts with VPS35. Interacts (via extracellular domain) with NTRK2 (via extracellular domain) (PubMed:27457814). Interacts with VPS35. Interacts (via extracellular domain) with GRIN2A (PubMed:28469074). Detected in Purkinje cells and pyramidal neurons in brain cortex, cerebellum, dentate gyrus, striatum and hippocampus, and in glia cells in dorsal root ganglia (DRG) (PubMed:24908487, PubMed:27457814, PubMed:28469074, PubMed:30840898). Not detected in neurons from the dorsal root ganglia (PubMed:24908487). Detected in hair cells and supporting cells in the organ of Corti, utricuar maculae and cristae (at protein level) (PubMed:28346477). Detected in brain, lung and testis (PubMed:11165493). Detected in the inner ear in neonates (PubMed:28346477). Expression is highest in developing brain. Transiently expressed in all 3 germ layers (PubMed:11165493). Detected in midbrain, spinal cord, heart and lung at 15.5 dpc (PubMed:24908487). Coexpressed with NGFR in neurons in the ventral part of the hippocampus CA1 region at 23 and 30 days after birth. The number of neurons that coexpress SORCS2 and NGFR is increased 30 days after birth. SORCS2 and NGFR are no longer coexpressed in hippocampus neurons in 60 day old adults (PubMed:29909994). N-glycosylated. Proteolytic cleavage removes a propeptide, giving rise to a 122 kDa chain that includes a cytoplasmic tail. Further cleavage gives rise to a 104 kDa chain that lacks the cytoplasmic tail, and a membrane-bound 18 kDa chain (PubMed:24908487). The 104 kDa chain remains bound to the 18 kDa chain (By similarity). Mice are viable and fertile and display no obvious phenotype, but their neurons do not display growth cone collapse in response to proBDNF (PubMed:24908487, PubMed:29909994). Cultured neurons from mutant mice display longer neurites than wild-type neurons, and the frontal cortex of 12 week old mice is hyperinnervated with fibers from tyrosine hydroxylase-positive neurons (PubMed:24908487, PubMed:29909994). Mutant mice display mildly increased spontaneous locomotor activity; contrary to wild-type, treatment with amphetamine decreases their locomotor activity. After sciatic nerve injury, 2 day old and adult mice show discreased Schwann cell apoptosis distal to the lesion (PubMed:24908487). Mutant mice show increased mortality after seizures caused by repeated treatments with the convulsant pentylenetetrazol (PTZ). Hippocampus neurons from mutant mice display increased levels of oxidative stress and increased apoptosis (PubMed:30840898). Mutant mice display subtle behavorial defects, with hyperactivity, altered acquisition of spatial memory, but a normal startle response to noise (PubMed:27457814). Heterozygous mice have normal body weight and motor skills, but combination with a mouse model for Huntington disease (HD) gives rise to increased severity of impaired motor skills (PubMed:28469074). After a cross of mice carrying a Cre construct under the control of the Tek promoter with mice carrying a floxed Nppc gene a subset of the offspring displayed behavorial defects, including hyperactivity and hanging from cage tops. A subset (11 out of 33 mice) displayed strongly reduced body weight and profound deafness, with defects in the organization of the outer and inner hair cell bundles in the organ of Corti. Analysis of the genomic DNA from deaf mice showed that in 13 cases, these mice had the Cre construct inserted into the first intron of the Sorcs2 gene, but in 21 cases, the insertion had occured in an Ig kappa locus (PubMed:28346477). SORCS2 expression is decreased after the onset of symptoms in mouse models for Huntington disease (HD). SORCS2 does not interact with wild-type HTT, but does interact with mutant HTT containing a long polyglutamine stretch. Belongs to the VPS10-related sortilin family. SORCS subfamily. Gene disruption gives rise to contradictory results (PubMed:24908487, PubMed:27457814, PubMed:28469074, PubMed:28346477, PubMed:30840898). The majority of studies report normal body weight, normal startle responses to noise and relatively minor behavorial defects (PubMed:24908487, PubMed:27457814, PubMed:28469074, PubMed:30840898). Another publication finds that gene disruption gives rise to mice with strongly reduced body weight and profound deafness. Gene disruption was due to random insertion of a Cre construct under the control of the TEK promoter. Analysis of the genomic DNA showed that in 21 cases the Cre construct had inserted in an Ig kappa locus, and in 13 cases the construct had inserted into the first intron of the SORCS2 gene, leading to strongly reduced SORCS2 expression (PubMed:28346477). The reasons for these discrepancies are not clear, but may be due to the way the experiments were done. The fact that an identical phenotype was found when the Cre construct under the control of the TEK promoter had inserted in an Ig kappa locus suggests that there are additional, unidentified causes that play a role in the observed defects.