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A detailed overview of the samples can be found in Fig. 1c, and Suppl. Figs. S1-3. The samples were freshly prepared and directly loaded onto 10% polyacrylamide SDS-PAGE gels, which were subsequently silver-stained. Each gel lane was divided into 20 bands, and de-stained in 50 mM ammonium bicarbonate and 50% acetonitrile. Proteins were reduced in 10 mM DTT, alkylated in 55 mM iodoacetamide, and dehydrated in 100% acetonitrile, using a liquid-handling robot (MultiProbe II, Perkin Elmer). Gel pieces were dehydrated in 100% acetonitrile, followed by tryptic digestion overnight using 13 ng/µl trypsin at 37 °C. Extracted peptides from consecutive bands were pooled into two MS/MS runs per lane based on protein saturation. Peptides were analyzed as described previously63. Briefly, nano-LC-MS/MS analysis was carried out using an Easy-nLC system (Thermo Scientific) directly coupled to an Orbitrap Q Exactive mass spectrometer (Thermo Scientific). Peptide separation was performed on a 10-cm fused SilicaTip column (New Objective, Inc.) packed in-house with 3-µm C18-AQ ReproSil-Pur (Dr. Maisch GmbH). Peptides were eluted using a linear gradient from 3% to 48% acetonitrile over 89 min at a flow rate of 300 nl/min. MS acquisition consisted of a full survey scan covering m/z 300–1650, acquired at a resolution of R = 70,000 at m/z 400, followed by up to ten data-dependent HCD MS/MS scans targeting the ten most abundant precursor ions with charge states ≥2, acquired at a resolution of R = 17,500.PrideNot availableTandem mass spectra were extracted using Raw2MGF (in-house software, Karolinska Institutet) and searched against the mouse SwissProt protein database (version 2012.03) using Mascot Daemon 2.3.02 (Matrix Science Ltd.). Search parameters included trypsin cleavage (allowing two missed sites), a peptide mass tolerance of 10 ppm, and a fragment ion tolerance of 0.05 Da. Fixed modifications included carbamidomethylation of cysteine, while variable modifications included methionine oxidation and asparagine/glutamine deamidation. Proteins were identified with a Mascot score threshold of 20, a significance threshold of 0.02, and MudPit scoring. Data were filtered to include only proteins meeting these criteria, with results exported for further analysis. Data analysis: Specific Ror2 binding partners were identified by comparison to IgG controls (Suppl. Table S1). IP-specific hits were generated by subtracting proteins also found in the IgG controls (“-IgG”) (Suppl. Table S2). A total of 625 recurrent Ror2 binding partners were detected in at least two replicates (Suppl. Table S3). Protein IDs were converted to UniProt identifiers using PANTHER database (version 19.0)105 and analyzed via DAVID106 for gene ontology (GO) and KEGG pathway enrichment, with 58% – 93% of proteins annotated in DAVID. Only GO terms with P value < 0.05 were considered significant (Suppl. Tables S5-6).ProteomicsMassimiliano GaetaniPARTIAL1 Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 177 Stockholm, Sweden 2 Chemical Proteomics Unit, Science for Life Laboratory (SciLifeLab), SE-17 177 Stockholm, Sweden 3 Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), SE-17 177 Stockholm, SwedenMus Musculus (mouse)Not availablemassimiliano.gaetani@ki.seKarolinska InstitutetSwedenfalseSorCS2 controls Wnt signaling homeostasis during neurodevelopment by regulating Ror2 activity and traffickingWnt signaling orchestrates key developmental processes, yet mechanisms restricting its spatial and temporal activity remain incompletely understood. Here we identify SorCS2, a VPS10p-domain sorting receptor, as a conserved regulator of Wnt signaling homeostasis. Integrating proteomics, cell biology, embryology, and vertebrate models, we show that SorCS2 interacts with the noncanonical Wnt receptor Ror2 and controls its trafficking, Wnt5a-induced internalization, and lysosomal degradation. In mouse dopaminergic progenitors, SorCS2 deficiency enhances responsiveness to canonical and noncanonical Wnt ligands, increases Ror2 phosphorylation, and amplifies downstream signaling of both Wnt signaling cascades. Loss of SorCS2 further disrupts the ligand-receptor feedback loop, leading to elevated Ror2, Wnt5a, and Wnt1 expression, accelerated proliferation and neurogenesis, and increased expression of Tcf4, a gene implicated in neuropsychiatric disorders. Across vertebrate systems, SorCS2-dependent control of Ror2 signaling is required for anterior-posterior axis elongation, convergent extension, somitogenesis, and brain morphogenesis. These findings define a SorCS2-dependent sorting mechanism that fine-tunes morphogen receptor signaling during vertebrate neurodevelopment.2026-10-022026-10-01PXD085067NEWT:6945NEWT:3555NEWT:2NEWT:157546NEWT:35554NEWT:9417NEWT:347515NEWT:1216979NEWT:307972NEWT:544496NEWT:5180NEWT:115104NEWT:1081927NEWT:67825NEWT:13076NEWT:1249668NEWT:376741NEWT:317NEWT:1736309NEWT:7227NEWT:7469NEWT:885318NEWT:4081NEWT:876138NEWT:554NEWT:98334NEWT:237561NEWT:10036NEWT:7574NEWT:1351NEWT:7215NEWT:272563NEWT:79220NEWT:507601NCBITaxon:79857NEWT:95648NEWT:746360NEWT:6239NEWT:1589NEWT:470150NEWT:135622NEWT:216257NEWT:6915NEWT:9986NEWT:101510NEWT:3880NEWT:1000589NEWT:1902NEWT:85962NEWT:160488NEWT:317447NEWT:7955NCBITaxon:2NEWT:985076NEWT:7959NEWT:2261NEWT:623NEWT:4565NEWT:1264690NCBITaxon:38727NEWT:34305NEWT:59729NCBITaxon:183674NEWT:224308NEWT:626528NEWT:139927NEWT:4558NEWT:209285NEWT:211586NEWT:243230NEWT:931281NEWT:7029NEWT:1283300NEWT:334747NCBITaxon:79824NCBITaxon:4563NEWT:5755NEWT:3218NEWT:5759NEWT:1736231NEWT:436486NEWT:6287NEWT:2242NEWT:9796NEWT:725NEWT:260707NEWT:287NEWT:10117NEWT:10239NEWT:10116NEWT:1280NEWT:1836NEWT:1735272NEWT:29760NEWT:260705NEWT:80863NEWT:1148NEWT:11676NEWT:55571NEWT:100226NCBITaxon:6073NEWT:4530NEWT:4896NEWT:6279NEWT:7370NEWT:6282NEWT:1134506NEWT:575584NEWT:1773NEWT:38783NEWT:8727NEWT:1182590NEWT:8726NEWT:10090NEWT:935293NEWT:749200NEWT:4120NEWT:5693NEWT:8724NEWT:51511NEWT:92867NEWT:8723NEWT:990346NEWT:5334NEWT:145953NEWT:257309NEWT:284812NCBITaxon:1313NEWT:43330NEWT:242619NEWT:44544NEWT:373995NEWT:544404NEWT:3702NEWT:129249NEWT:8839NEWT:4232NEWT:990119NEWT:4113NEWT:11298NEWT:171101NEWT:196627NEWT:5691NEWT:408170NEWT:493760NEWT:260710NEWT:627025NEWT:400772NEWT:3708NEWT:106592NEWT:9913NEWT:1432138NEWT:10312NEWT:4100NEWT:1076NEWT:6763NEWT:3498NEWT:803NEWT:8030NEWT:380394NEWT:1639NEWT:188229NEWT:4909NEWT:135588NEWT:1843183NEWT:95486NEWT:58002NEWT:9103NEWT:4577NEWT:5664NEWT:2157NEWT:146479NEWT:10306NEWT:1911079NEWT:145943NCBITaxon:620NEWT:3635NEWT:235443NEWT:1480154NEWT:3197NEWT:9615NEWT:10299NEWT:2719099NEWT:884019NEWT:169963NEWT:36329NEWT:9606NEWT:367830NEWT:157295NEWT:373153NEWT:915099NEWT:470NEWT:84023NEWT:9838NCBITaxon:9615NEWT:1193501NEWT:3055NEWT:6326NEWT:2762NEWT:5476NEWT:1174673NEWT:562NEWT:4932NEWT:70448NEWT:9825NEWT:3603NEWT:698936NEWT:2759NEWT:39946NEWT:9823NEWT:573NEWT:70910000-0001-5610-0797