{"gene":"SCAMP4","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2000,"finding":"SCAMP4 is an integral membrane protein (~25 kDa) that lacks most of the N-terminal hydrophilic domain present in other SCAMP family members (including NPF repeats, leucine heptad repeat, and proline-rich SH3-like/WW domain-binding sites), yet retains the conserved four-transmembrane-span membrane core. Its authenticity was confirmed by Northern and Western blotting, suggesting the membrane core encodes the functional domain.","method":"DNA sequencing, Northern blotting, Western blotting, structural domain analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Northern, Western) in a single lab establishing structural features","pmids":["10982391"],"is_preprint":false},{"year":2001,"finding":"SCAMP4 localizes to distinct subcellular aggregates consistent with secretory vesicles when expressed as a GFP fusion construct in transfected cells, and is the only SCAMP family member identified to contain a putative protein kinase C (PKC) phosphorylation site.","method":"Fluorescence microscopy of SCAMP4/GFP fusion construct in transfected cells; amino acid sequence analysis","journal":"Brain research. Molecular brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single localization method without functional validation of vesicle identity or PKC phosphorylation","pmids":["11295240"],"is_preprint":false},{"year":2001,"finding":"SCAMP4 mRNA expression is repressed by progesterone in the ventromedial hypothalamus (VMH) of female rats primed with estrogen, as demonstrated by differential display-PCR and Northern blotting, placing SCAMP4 as a genomic target of progesterone signaling in neuroendocrine brain regions.","method":"Differential display-PCR, Northern blotting, in situ hybridization","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (differential display-PCR, Northern blot, in situ hybridization) in single lab","pmids":["11295240"],"is_preprint":false},{"year":2018,"finding":"SCAMP4 protein levels are strikingly elevated on the surface of senescent cells compared with proliferating cells (detected by mass spectrometry), and SCAMP4 promotes secretion of SASP factors (IL6, IL8, GDF-15, CXCL1, IL7): silencing SCAMP4 in senescent fibroblasts reduced SASP factor secretion, while overexpression of SCAMP4 in proliferating fibroblasts increased SASP factor secretion.","method":"Mass spectrometry (surface protein profiling), siRNA-mediated silencing, overexpression in fibroblasts, cytokine secretion assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with specific secretion readouts, mass spectrometry for localization, multiple SASP factors measured","pmids":["29967290"],"is_preprint":false}],"current_model":"SCAMP4 is a small (~25 kDa) integral membrane protein lacking most N-terminal domains of other SCAMP family members that localizes to the cell surface of senescent cells, where it functions as a positive regulator of the senescence-associated secretory phenotype (SASP) by promoting secretion of pro-inflammatory cytokines and growth factors; its expression is also subject to hormonal regulation (repressed by progesterone) in neuroendocrine brain regions."},"narrative":{"mechanistic_narrative":"SCAMP4 is a small integral membrane protein that functions as a positive regulator of the senescence-associated secretory phenotype (SASP) at the cell surface [PMID:29967290]. It retains the conserved four-transmembrane-span membrane core common to the SCAMP family but lacks most of the N-terminal hydrophilic domain found in other members, implying that its functional activity resides in the membrane core [PMID:10982391]. When ectopically expressed, it concentrates in subcellular aggregates consistent with secretory vesicles [PMID:11295240]. In senescent fibroblasts its levels rise markedly at the cell surface, and reciprocal loss- and gain-of-function experiments establish that SCAMP4 promotes secretion of pro-inflammatory SASP factors including IL6, IL8, GDF-15, CXCL1, and IL7 [PMID:29967290]. Independently of this secretory role, SCAMP4 mRNA is a genomic target of progesterone signaling, being repressed by progesterone in the estrogen-primed ventromedial hypothalamus [PMID:11295240]. Beyond these findings, the biochemical mechanism by which SCAMP4 controls secretory cargo release has not been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Established that SCAMP4 is a structurally distinct SCAMP family member, raising the question of where its function is encoded given its truncated N-terminus.","evidence":"DNA sequencing, Northern and Western blotting, and structural domain analysis of the protein","pmids":["10982391"],"confidence":"Medium","gaps":["No functional assay tied the membrane core to a specific molecular activity","No subcellular localization established at this stage","Whether the N-terminal truncation alters trafficking or partner binding was not tested"]},{"year":2001,"claim":"Provided the first localization clue and a candidate regulatory site, implicating SCAMP4 in secretory vesicle biology and possible PKC regulation.","evidence":"Fluorescence microscopy of a SCAMP4/GFP fusion in transfected cells plus sequence analysis identifying a putative PKC phosphorylation site","pmids":["11295240"],"confidence":"Low","gaps":["Single localization method without validation of vesicle identity","The putative PKC site was predicted, not shown to be phosphorylated","GFP-fusion overexpression may not reflect endogenous distribution"]},{"year":2001,"claim":"Placed SCAMP4 within hormonal signaling by showing its transcript is a progesterone-repressed gene in neuroendocrine tissue, defining a regulatory input on its expression.","evidence":"Differential display-PCR, Northern blotting, and in situ hybridization in the ventromedial hypothalamus of estrogen-primed female rats","pmids":["11295240"],"confidence":"Medium","gaps":["Mechanism of progesterone-dependent repression (direct vs indirect) not resolved","Functional consequence of altered SCAMP4 levels in the hypothalamus untested","Whether this regulation occurs in non-neural tissues unknown"]},{"year":2018,"claim":"Defined SCAMP4's cellular function by linking its surface accumulation in senescent cells to active promotion of SASP factor secretion, establishing it as a positive regulator of the secretory phenotype.","evidence":"Mass spectrometry surface profiling, siRNA silencing, and overexpression in fibroblasts with cytokine secretion readouts","pmids":["29967290"],"confidence":"High","gaps":["Molecular mechanism by which SCAMP4 drives cargo secretion not defined","Direct physical partners in the secretory machinery not identified","Whether the same activity operates outside senescent fibroblasts untested"]},{"year":null,"claim":"The biochemical mechanism connecting SCAMP4's membrane core to secretory cargo selection and release, and any direct interaction partners, remain undetermined.","evidence":"","pmids":[],"confidence":"High","gaps":["No identified direct binding partners in the trafficking machinery","No structural model of the functional membrane core","No reconstitution of SCAMP4-dependent secretion"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969E2","full_name":"Secretory carrier-associated membrane protein 4","aliases":[],"length_aa":229,"mass_kda":25.7,"function":"Probably involved in membrane protein trafficking","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q969E2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCAMP4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000227500","cell_line_id":"CID000081","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"RAB11B","stoichiometry":4.0},{"gene":"RAB14","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000081","total_profiled":1310},"omim":[{"mim_id":"613764","title":"SECRETORY CARRIER MEMBRANE PROTEIN 4; SCAMP4","url":"https://www.omim.org/entry/613764"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Lipid droplets","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCAMP4"},"hgnc":{"alias_symbol":["FLJ33847"],"prev_symbol":[]},"alphafold":{"accession":"Q969E2","domains":[{"cath_id":"1.20.120","chopping":"31-179","consensus_level":"high","plddt":96.1436,"start":31,"end":179}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969E2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969E2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969E2-F1-predicted_aligned_error_v6.png","plddt_mean":86.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCAMP4","jax_strain_url":"https://www.jax.org/strain/search?query=SCAMP4"},"sequence":{"accession":"Q969E2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969E2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969E2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969E2"}},"corpus_meta":[{"pmid":"22933518","id":"PMC_22933518","title":"Small RNA profile of the cumulus-oocyte complex and early embryos in the pig.","date":"2012","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/22933518","citation_count":69,"is_preprint":false},{"pmid":"10982391","id":"PMC_10982391","title":"The secretory carrier membrane protein family: structure and membrane topology.","date":"2000","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10982391","citation_count":51,"is_preprint":false},{"pmid":"29967290","id":"PMC_29967290","title":"SCAMP4 enhances the senescent cell secretome.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29967290","citation_count":40,"is_preprint":false},{"pmid":"11295240","id":"PMC_11295240","title":"Expression of the SCAMP-4 gene, a new member of the secretory carrier membrane protein family, is repressed by progesterone in brain regions associated with female sexual behavior.","date":"2001","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11295240","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4317,"output_tokens":1050,"usd":0.014351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7595,"output_tokens":1737,"usd":0.0407,"stage2_stop_reason":"end_turn"},"total_usd":0.055051,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SCAMP4 is an integral membrane protein (~25 kDa) that lacks most of the N-terminal hydrophilic domain present in other SCAMP family members (including NPF repeats, leucine heptad repeat, and proline-rich SH3-like/WW domain-binding sites), yet retains the conserved four-transmembrane-span membrane core. Its authenticity was confirmed by Northern and Western blotting, suggesting the membrane core encodes the functional domain.\",\n      \"method\": \"DNA sequencing, Northern blotting, Western blotting, structural domain analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Northern, Western) in a single lab establishing structural features\",\n      \"pmids\": [\"10982391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SCAMP4 localizes to distinct subcellular aggregates consistent with secretory vesicles when expressed as a GFP fusion construct in transfected cells, and is the only SCAMP family member identified to contain a putative protein kinase C (PKC) phosphorylation site.\",\n      \"method\": \"Fluorescence microscopy of SCAMP4/GFP fusion construct in transfected cells; amino acid sequence analysis\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single localization method without functional validation of vesicle identity or PKC phosphorylation\",\n      \"pmids\": [\"11295240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SCAMP4 mRNA expression is repressed by progesterone in the ventromedial hypothalamus (VMH) of female rats primed with estrogen, as demonstrated by differential display-PCR and Northern blotting, placing SCAMP4 as a genomic target of progesterone signaling in neuroendocrine brain regions.\",\n      \"method\": \"Differential display-PCR, Northern blotting, in situ hybridization\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (differential display-PCR, Northern blot, in situ hybridization) in single lab\",\n      \"pmids\": [\"11295240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCAMP4 protein levels are strikingly elevated on the surface of senescent cells compared with proliferating cells (detected by mass spectrometry), and SCAMP4 promotes secretion of SASP factors (IL6, IL8, GDF-15, CXCL1, IL7): silencing SCAMP4 in senescent fibroblasts reduced SASP factor secretion, while overexpression of SCAMP4 in proliferating fibroblasts increased SASP factor secretion.\",\n      \"method\": \"Mass spectrometry (surface protein profiling), siRNA-mediated silencing, overexpression in fibroblasts, cytokine secretion assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with specific secretion readouts, mass spectrometry for localization, multiple SASP factors measured\",\n      \"pmids\": [\"29967290\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCAMP4 is a small (~25 kDa) integral membrane protein lacking most N-terminal domains of other SCAMP family members that localizes to the cell surface of senescent cells, where it functions as a positive regulator of the senescence-associated secretory phenotype (SASP) by promoting secretion of pro-inflammatory cytokines and growth factors; its expression is also subject to hormonal regulation (repressed by progesterone) in neuroendocrine brain regions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCAMP4 is a small integral membrane protein that functions as a positive regulator of the senescence-associated secretory phenotype (SASP) at the cell surface [#3]. It retains the conserved four-transmembrane-span membrane core common to the SCAMP family but lacks most of the N-terminal hydrophilic domain found in other members, implying that its functional activity resides in the membrane core [#0]. When ectopically expressed, it concentrates in subcellular aggregates consistent with secretory vesicles [#1]. In senescent fibroblasts its levels rise markedly at the cell surface, and reciprocal loss- and gain-of-function experiments establish that SCAMP4 promotes secretion of pro-inflammatory SASP factors including IL6, IL8, GDF-15, CXCL1, and IL7 [#3]. Independently of this secretory role, SCAMP4 mRNA is a genomic target of progesterone signaling, being repressed by progesterone in the estrogen-primed ventromedial hypothalamus [#2]. Beyond these findings, the biochemical mechanism by which SCAMP4 controls secretory cargo release has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that SCAMP4 is a structurally distinct SCAMP family member, raising the question of where its function is encoded given its truncated N-terminus.\",\n      \"evidence\": \"DNA sequencing, Northern and Western blotting, and structural domain analysis of the protein\",\n      \"pmids\": [\"10982391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay tied the membrane core to a specific molecular activity\",\n        \"No subcellular localization established at this stage\",\n        \"Whether the N-terminal truncation alters trafficking or partner binding was not tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided the first localization clue and a candidate regulatory site, implicating SCAMP4 in secretory vesicle biology and possible PKC regulation.\",\n      \"evidence\": \"Fluorescence microscopy of a SCAMP4/GFP fusion in transfected cells plus sequence analysis identifying a putative PKC phosphorylation site\",\n      \"pmids\": [\"11295240\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single localization method without validation of vesicle identity\",\n        \"The putative PKC site was predicted, not shown to be phosphorylated\",\n        \"GFP-fusion overexpression may not reflect endogenous distribution\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed SCAMP4 within hormonal signaling by showing its transcript is a progesterone-repressed gene in neuroendocrine tissue, defining a regulatory input on its expression.\",\n      \"evidence\": \"Differential display-PCR, Northern blotting, and in situ hybridization in the ventromedial hypothalamus of estrogen-primed female rats\",\n      \"pmids\": [\"11295240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of progesterone-dependent repression (direct vs indirect) not resolved\",\n        \"Functional consequence of altered SCAMP4 levels in the hypothalamus untested\",\n        \"Whether this regulation occurs in non-neural tissues unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined SCAMP4's cellular function by linking its surface accumulation in senescent cells to active promotion of SASP factor secretion, establishing it as a positive regulator of the secretory phenotype.\",\n      \"evidence\": \"Mass spectrometry surface profiling, siRNA silencing, and overexpression in fibroblasts with cytokine secretion readouts\",\n      \"pmids\": [\"29967290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which SCAMP4 drives cargo secretion not defined\",\n        \"Direct physical partners in the secretory machinery not identified\",\n        \"Whether the same activity operates outside senescent fibroblasts untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism connecting SCAMP4's membrane core to secretory cargo selection and release, and any direct interaction partners, remain undetermined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No identified direct binding partners in the trafficking machinery\",\n        \"No structural model of the functional membrane core\",\n        \"No reconstitution of SCAMP4-dependent secretion\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}