SCAMP3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006887 exocytosis	IBA GO_REF:0000033	MODIFY	Summary: This IBA annotation derives from phylogenetic inference across the SCAMP family. While SCAMP3 is involved in vesicular trafficking pathways, the primary experimental evidence supports its role in endosomal sorting and MVB biogenesis rather than classical exocytosis. The original SCAMP1/2 literature focused on post-Golgi recycling carriers, but SCAMP3-specific studies emphasize EGFR trafficking and intralumenal vesicle formation (PMID:19158374). Reason: The term 'exocytosis' is too general and does not capture the specific role of SCAMP3. The deep research indicates SCAMP3 functions primarily in endosomal sorting, MVB biogenesis, and regulation of receptor recycling vs degradation rather than classical exocytosis. A more appropriate term would be 'post-Golgi vesicle-mediated transport' (which already exists as another annotation) or 'endosomal transport'. Proposed replacements: endosomal transport Supporting Evidence: PMID:19158374 SCAMP3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling file:human/SCAMP3/SCAMP3-deep-research-falcon.md model: Edison Scientific Literature
GO:0032588 trans-Golgi network membrane	IBA GO_REF:0000033	ACCEPT	Summary: This IBA annotation is consistent with experimental findings. The deep research indicates SCAMP3 localizes to the Golgi apparatus, and the original 1997 paper (PMID:9378760) showed SCAMPs have similar subcellular distributions including Golgi-associated compartments. The 2012 Traffic paper confirmed SCAMP3 localization to Golgi and endosomal compartments. Reason: The annotation accurately reflects SCAMP3 localization. Literature demonstrates SCAMP3 presence at Golgi and trans-Golgi network membranes consistent with its role in post-Golgi trafficking. Supporting Evidence: PMID:9378760 Examination of the codistribution of the three forms within individual cells using double label immunofluorescence indicates extensive colocalization of SCAMP2 and SCAMP3 with endogenous SCAMP1
GO:0055038 recycling endosome membrane	IBA GO_REF:0000033	ACCEPT	Summary: This IBA annotation is well-supported by experimental evidence. SCAMP3 promotes receptor recycling and localizes to endosomal compartments including recycling endosomes. The 2009 Mol Biol Cell paper demonstrated that SCAMP3 promotes EGFR recycling rather than degradation (PMID:19158374). Reason: The annotation accurately reflects SCAMP3 localization and function. SCAMP3 functions as a recycling carrier and promotes receptor recycling from endosomal compartments back to the plasma membrane. Supporting Evidence: PMID:19158374 SCAMP3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling
GO:0015031 protein transport	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation inferred from InterPro domain and UniProtKB keywords is accurate but very general. SCAMP3 is indeed involved in protein transport through its role in vesicular trafficking, EGFR sorting, and MVB pathway regulation. Reason: The annotation is correct but represents a high-level term. More specific annotations like post-Golgi vesicle-mediated transport and endosomal transport better capture SCAMP3 function. However, this IEA annotation is not incorrect and provides appropriate coverage. Supporting Evidence: PMID:9378760 The SCAMPs may largely function at the same sites during vesicular transport rather than in separate post-Golgi recycling pathways
GO:0016020 membrane	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation is correct. SCAMP3 is a tetraspanning integral membrane protein with four transmembrane helices (residues 171-191, 197-217, 247-267, 277-297) according to UniProt annotation. Reason: The annotation is accurate. SCAMP3 is clearly a membrane protein with four transmembrane domains. More specific membrane localizations (trans-Golgi network membrane, recycling endosome membrane) are captured in other annotations. Supporting Evidence: PMID:9378760 SCAMPs are highly related products of distinct genes
GO:0031625 ubiquitin protein ligase binding	IPI PMID:23418353 The E3 ubiquitin ligases RNF126 and Rabring7 regulate endoso...	ACCEPT	Summary: This IPI annotation is well-supported. SCAMP3 contains a PPAY motif that binds WW-domain E3 ubiquitin ligases including NEDD4 and NEDD4L. The UniProt entry confirms interactions with NEDD4, NEDD4L, TSG101, and RNF126. The cited paper (PMID:23418353) demonstrates SCAMP3 interaction with RNF126 E3 ubiquitin ligase. Reason: The annotation accurately reflects SCAMP3's molecular function. The PPAY motif mediates binding to WW-domain containing E3 ubiquitin ligases. This interaction is functionally important for SCAMP3's role in endosomal sorting and receptor trafficking. Supporting Evidence: PMID:23418353 We also show that the depletion of Rabring7 attenuates the degradation of MET and that both RNF126 and Rabring7 regulate the sorting of CXCR4 from an early endocytic compartment PMID:19158374 SCAMP3 is multimonoubiquitylated and is able to associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit Tsg101 via its PY and PSAP motifs, respectively
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	ACCEPT	Summary: This HDA annotation from high-throughput proteomics is strongly supported by recent functional studies. The 2023 Science Advances paper demonstrated that SCAMP3 is essential for WW domain-activated extracellular vesicle (WAEV) budding. SCAMP3 knockout nearly abolishes EV production measured by NanoSight, and only wild-type (not PPAY mutant) SCAMP3 can rescue this phenotype. Reason: The annotation is experimentally validated by multiple studies. SCAMP3 was identified in B-cell exosome proteomics and later shown to be functionally required for extracellular vesicle biogenesis through its PPAY-WW domain interactions. Supporting Evidence: PMID:20458337 We first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins
GO:0006892 post-Golgi vesicle-mediated transport	TAS PMID:9378760 Three mammalian SCAMPs (secretory carrier membrane proteins)...	ACCEPT	Summary: This TAS annotation from the original SCAMP characterization paper is well-supported. The 1997 paper established that SCAMPs function in post-Golgi recycling pathways, and subsequent studies have confirmed SCAMP3's role in trafficking from Golgi through endosomal compartments. Reason: The annotation accurately reflects a core function of SCAMP3. The protein functions in post-Golgi vesicular transport, mediating carrier function between Golgi, endosomal compartments, and plasma membrane. Supporting Evidence: PMID:9378760 These findings suggest that the SCAMPs may largely function at the same sites during vesicular transport rather than in separate post-Golgi recycling pathways
GO:0070676 intralumenal vesicle formation	IDA file:human/SCAMP3/SCAMP3-deep-research-falcon.md	NEW	Summary: NEW annotation supported by direct experimental evidence. The 2012 Traffic paper demonstrated that SCAMP3 knockdown significantly reduces intralumenal vesicle (ILV) formation in multivesicular bodies (stereological analysis, p<0.0001). SCAMP3 is required for cargo sorting into ILVs and MVB biogenesis. Reason: Strong experimental evidence supports this annotation. SCAMP3 is required for ILV formation through its interaction with ESCRT machinery via the PSAP-TSG101 and PPAY-WW domain interactions. Supporting Evidence: PMID:19158374 SCAMP3, its modification with ubiquitin, and its interactions with ESCRTs coordinately regulate endosomal pathways and affect the efficiency of receptor down-regulation
GO:0005770 late endosome	IDA file:human/SCAMP3/SCAMP3-deep-research-falcon.md	NEW	Summary: NEW annotation supported by experimental evidence. The 2012 Traffic paper demonstrated that approximately 30% of late endosomes contain SCAMP3 based on quantitative image analysis. SCAMP3 localizes to a subset of late endosomes/MVBs. Reason: Direct evidence from immunofluorescence and EM studies shows SCAMP3 localization to late endosomal compartments where it functions in cargo sorting and ILV formation. Supporting Evidence: PMID:19158374 SCAMP3 depletion appeared to sustain the incidence of EGFR-containing MVBs detected by immunoelectron microscopy
GO:0001881 receptor recycling	IMP PMID:19158374 SCAMP3 negatively regulates epidermal growth factor receptor...	NEW	Summary: NEW annotation supported by experimental evidence. The 2009 Mol Biol Cell paper demonstrated that SCAMP3 promotes EGFR recycling. SCAMP3 overexpression enhanced EGFR recycling while knockdown accelerated degradation and impaired recycling. Reason: Strong experimental evidence from mutant analysis shows SCAMP3 functions in promoting receptor recycling, balancing recycling vs degradation fate. Supporting Evidence: PMID:19158374 Depletion of SCAMP3 in HeLa cells by inhibitory RNA accelerated degradation of EGFR and EGF while inhibiting recycling
GO:0032585 multivesicular body membrane	IDA file:human/SCAMP3/SCAMP3-deep-research-falcon.md	NEW	Summary: NEW annotation supported by experimental evidence. SCAMP3 localizes to and functions at MVB membranes, where it is required for ILV formation and cargo sorting. Reason: SCAMP3 localization to MVB membranes is demonstrated through its role in MVB biogenesis and ESCRT-dependent sorting. Supporting Evidence: PMID:19158374 SCAMP3 depletion appeared to sustain the incidence of EGFR-containing MVBs detected by immunoelectron microscopy

Core Functions

SCAMP3 functions as a multi-modal regulator of endosomal trafficking, controlling the fate of cargo proteins including EGFR between recycling and lysosomal degradation pathways through interactions with ESCRT machinery.

Molecular Function:

ubiquitin protein ligase binding

Directly Involved In:

endosomal transport intralumenal vesicle formation

Cellular Locations:

recycling endosome membrane multivesicular body membrane trans-Golgi network membrane

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

SCAMP3 identified in B-cell exosome proteome

"We first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins"

PMID:23418353

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor.

RNF126 and Rabring7 regulate EGFR endosomal sorting

"RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor"

PMID:9378760

Three mammalian SCAMPs (secretory carrier membrane proteins) are highly related products of distinct genes having similar subcellular distributions.

SCAMP3 characterized as member of SCAMP family

"Three mammalian SCAMPs (secretory carrier membrane proteins) are highly related products of distinct genes having similar subcellular distributions"
SCAMPs colocalize and function in post-Golgi recycling pathways

"These findings suggest that the SCAMPs may largely function at the same sites during vesicular transport rather than in separate post-Golgi recycling pathways"

PMID:19158374

SCAMP3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling.

SCAMP3 contains PPAY motif binding NEDD4 family E3 ligases

"SCAMP3 is multimonoubiquitylated and is able to associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit Tsg101 via its PY and PSAP motifs, respectively"
SCAMP3 is multi-monoubiquitinated

"SCAMP3 is multimonoubiquitylated"
SCAMP3 promotes EGFR recycling over degradation

"Depletion of SCAMP3 in HeLa cells by inhibitory RNA accelerated degradation of EGFR and EGF while inhibiting recycling"
SCAMP3 interacts with NEDD4, NEDD4L, and TSG101

"SCAMP3 is multimonoubiquitylated and is able to associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit Tsg101 via its PY and PSAP motifs, respectively"

file:human/SCAMP3/SCAMP3-deep-research-falcon.md

Deep research on SCAMP3 function

SCAMP3 required for ILV formation in MVBs based on 2012 Traffic paper
SCAMP3 localizes to late endosomes based on immunofluorescence studies

Suggested Experiments

Experiment: Structure-function analysis of SCAMP3 using site-directed mutagenesis of the ubiquitination sites to determine how ubiquitination state affects recycling vs degradation outcomes. This could resolve the apparent discrepancy between SCAMP3's role in promoting recycling versus driving lysosomal degradation.

Deep Research

Falcon

(SCAMP3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 22 citations 2025-12-27T23:38:03.641167

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan
- Verified target identity and nomenclature.
- Retrieved and synthesized recent primary literature (priority 2023–2024) and authoritative sources on SCAMP3.
- Extracted mechanistic evidence on localization, motifs, post-translational modifications, interacting partners, and trafficking functions.
- Summarized recent developments in EV technology, cancer biology, and infection/immunity.
- Compiled quantitative findings and created a summary artifact.

Comprehensive research report: SCAMP3 (Human; UniProt O14828)

1) Identity verification and core concepts
- Identity and organism: SCAMP3 (secretory carrier-associated membrane protein 3) is a human integral membrane protein in the SCAMP family (SCAMP1–5), with a characteristic tetraspanning topology and cytoplasmic N- and C-termini (Homo sapiens). Traffic-focused cell biology places SCAMP3 at the Golgi, early endosomes, and a subset of late endosomes; quantification indicates roughly 30% of late endosomes contain SCAMP3 (image analysis) (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 1-2).
- Domain/motif architecture and ubiquitin linkage: SCAMP3 contains an N‑terminal proline-rich region with a PPAY motif (PY) that binds WW-domain E3 ligases (e.g., NEDD4-family) and a PSAP motif that binds ESCRT‑I subunit TSG101. SCAMP3 is multi‑monoubiquitylated. These features underlie its functional interactions in endosomal sorting and EGFR trafficking (2009-03; Mol Biol Cell; https://doi.org/10.1091/mbc.e08-09-0894) (aoh2009scamp3negativelyregulates pages 1-2, radic2016anovelrolea pages 44-49).
- Functional theme: SCAMP3 is a trafficking regulator at early-to-late endosomes/MVBs that tunes the balance of receptor recycling versus degradation and participates in intralumenal vesicle (ILV) formation via ESCRT-associated mechanisms (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 10-11, falguieres2012regulationofthe pages 7-9).

2) Molecular function, mechanisms, and localization
- Subcellular localization: SCAMP3 localizes to Golgi and early endosomes (coincident with Rab5/EEA1) and to a subset of late endosomes/lysosomes; limited surface presence has been detected. Approximately 30% of late endosomes are SCAMP3-positive (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 1-2).
- ESCRT-coupled sorting and motifs: The PSAP motif in SCAMP3 mediates binding to TSG101 (ESCRT‑I), and the PPAY motif engages WW-domain E3 ligases (e.g., NEDD4 family), with SCAMP3 itself being multi‑monoubiquitylated. SCAMP3 depletion accelerated EGFR/EGF degradation and impaired recycling, while overexpression enhanced recycling; these effects required SCAMP3 lysines and intact PSAP/PY motifs (2009-03; Mol Biol Cell; https://doi.org/10.1091/mbc.e08-09-0894) (aoh2009scamp3negativelyregulates pages 1-2).
- Role in MVB/ILV biogenesis: SCAMP3 is required for cargo sorting into ILVs and for EGF‑driven multivesicular endosome biogenesis; its knockdown reduces ILV formation (stereology over ~3000 μm² cytoplasm, p<0.0001), reduces cargo incorporation (HPTS/nanogold), and delays EGFR degradation (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 7-9).
- EGFR trafficking and resolution of apparent discrepancies: Early work showed SCAMP3 promotes EGFR recycling and limits degradation (2009). Later work emphasized SCAMP3’s necessity for ILV formation and lysosomal targeting of EGFR (2012). A 2016 synthesis suggested that differential SCAMP3 ubiquitination state or regulatory context could reconcile these findings (2016; preprint/unknown venue) (aoh2009scamp3negativelyregulates pages 1-2, falguieres2012regulationofthe pages 7-9, radic2016anovelrolea pages 44-49).

3) Post-translational modifications and regulatory switches
- Ubiquitination: SCAMP3 undergoes multiple monoubiquitinations; modulation of ubiquitylation likely toggles functions (e.g., ESCRT engagement vs recycling roles) (2009-03; Mol Biol Cell; https://doi.org/10.1091/mbc.e08-09-0894) (aoh2009scamp3negativelyregulates pages 1-2).
- Tyrosine phosphorylation by EGFR: Quantitative phosphoproteomics in lung adenocarcinoma identified SCAMP3 Tyr86 (and Tyr35) phosphorylation downstream of activated or mutant EGFR (L858R/T790M). Y86 phosphorylation enhances SCAMP3–EGFR interaction and is required for SCAMP3-driven EGFR degradation and tumor-suppressive phenotypes; Y86F fails to rescue degradation defects and growth phenotypes (2021-04; Oncogene; https://doi.org/10.1038/s41388-021-01764-y) (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10, venugopalan2021scamp3isa pages 1-2).

4) Interactors and pathway placement
- EGFR axis: SCAMP3 physically associates with EGFR upon activation and co-localizes in early endosomes/perinuclear compartments; phosphorylation at Y86 promotes this association (2021-04; Oncogene; https://doi.org/10.1038/s41388-021-01764-y; 2022-06; Cancers; https://doi.org/10.3390/cancers14112807) (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10, acevedodiaz2022scamp3regulatesegfr pages 9-13).
- ESCRT machinery: SCAMP3 engages TSG101 (ESCRT‑I) via PSAP and associates with HRS (ESCRT‑0), functionally linking to receptor sorting into ILVs (2009-03; Mol Biol Cell; https://doi.org/10.1091/mbc.e08-09-0894; 2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (aoh2009scamp3negativelyregulates pages 1-2, falguieres2012regulationofthe pages 7-9).
- WW-domain proteins and EV budding: SCAMP3’s PPAY motif binds WW domains to drive “WW domain–activated extracellular vesicles” (WAEVs); SCAMP3 knockout nearly abolishes WAEV budding, and re-expression of WT but not PPAY→PPAA mutant restores EV budding (2023-01; Sci Adv; https://doi.org/10.1126/sciadv.ade2708) (choi2023displayinganddelivering pages 2-3).
- Antiviral innate immunity: SCAMP3 stabilizes IFITM3 by decreasing its lysosomal degradation and alters endosome→Golgi retrograde transport; it physically interacts with IFITM3. Notably, SCAMP3 did not change IFITM3 ubiquitination pattern (2016; preprint/unknown venue) (radic2016anovelrolea pages 88-97, radic2016anovelrole pages 88-97).
- Viral replication complexes: SCAMP3 interacts with enterovirus 3A and co-assembles with PI4KIIIβ/PI4P at replication sites; SCAMP3 depletion decreases viral RNA/protein synthesis and viral growth (EV‑A71, CVB3) (2021-09; Microbiol Spectrum; https://doi.org/10.1128/spectrum.00475-21) (lu2021secretorycarriermembrane pages 10-11).

5) Recent developments (priority 2023–2024) and applications
- EV technology and vaccine design (2023): A WW-domain–activated EV platform requires SCAMP3; WW–PPAY interactions on SCAMP3 recruit cargo to EVs and drive budding. SCAMP3 knockout drastically reduces EV number (NanoSight) and eliminates WAEV budding; WT rescue restores budding, PPAY-mutant fails. This establishes SCAMP3 as an actionable EV-budding factor for membrane antigen vaccine delivery (2023-01; Sci Adv; https://doi.org/10.1126/sciadv.ade2708) (choi2023displayinganddelivering pages 2-3).
- Cancer signaling and trafficking control (2021–2022): In lung adenocarcinoma, SCAMP3 is a mutant EGFR phosphorylation target; Y86 phosphorylation is required for tumor-suppressive control of EGFR degradation and for preventing multinucleation and hyperproliferation (2021-04; Oncogene; https://doi.org/10.1038/s41388-021-01764-y) (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10). In TNBC, SCAMP3 controls EGFR trafficking and modulates AKT/ERK/STAT3 pathways; knockout reduces proliferation, migration, invasion, and delays early tumor growth in xenografts; high SCAMP3 associates with poorer outcomes in patient datasets (2022-06; Cancers; https://doi.org/10.3390/cancers14112807) (acevedodiaz2022scamp3regulatesegfr pages 7-9, acevedodiaz2022scamp3regulatesegfr pages 1-2, acevedodiaz2022scamp3regulatesegfr pages 19-21, acevedodiaz2022scamp3regulatesegfr pages 9-13).
- Infection biology (2021): SCAMP3’s role in enterovirus replication complexes supports broader functions in virus-driven membrane remodeling and lipid kinase recruitment (PI4KIIIβ/PI4P) (2021-09; Microbiol Spectrum; https://doi.org/10.1128/spectrum.00475-21) (lu2021secretorycarriermembrane pages 10-11).

6) Quantitative data and phenotypes
- Localization prevalence: ~30% of late endosomes are SCAMP3-positive (image analysis), with colocalization to early endosome markers (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 1-2).
- ILV/MVB formation: SCAMP3 knockdown significantly reduces ILV formation (stereological analysis across ~3000 μm² cytoplasm, p<0.0001); EGFR degradation is delayed (2012-01; Traffic; https://doi.org/10.1111/j.1600-0854.2011.01291.x) (falguieres2012regulationofthe pages 7-9).
- EGFR degradation kinetics and tumor phenotypes: In lung adenocarcinoma models, control cells show substantial EGFR degradation by ~30 min; SCAMP3-depleted cells exhibit delayed degradation (comparable only by ~2 h). SCAMP3 depletion increases pERK/pAKT, proliferation, colony formation, multinucleation; rescue by WT but not Y86F SCAMP3. Multinucleation assay counts: control n=1576; SCAMP3‑KD n=1132; rescue n=1283; Y86F n=1041 (2021-04; Oncogene; https://doi.org/10.1038/s41388-021-01764-y) (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10).
- EV production: SCAMP3-KO cells show a significant reduction in EV counts (NanoSight), with near-complete loss of WAEV budding; re-expressing WT but not PPAY-mutant (PPAA) restores budding (2023-01; Sci Adv; https://doi.org/10.1126/sciadv.ade2708) (choi2023displayinganddelivering pages 2-3).
- TNBC functional readouts: SCAMP3 knockout decreases proliferation at 72 h with EGF stimulation; reduces colony and tumorsphere formation, migration and invasion. Early in vivo xenograft growth is delayed; high SCAMP3 associates with reduced RFS/DMFS in TCGA analyses (2022-06; Cancers; https://doi.org/10.3390/cancers14112807) (acevedodiaz2022scamp3regulatesegfr pages 7-9, acevedodiaz2022scamp3regulatesegfr pages 1-2, acevedodiaz2022scamp3regulatesegfr pages 19-21, acevedodiaz2022scamp3regulatesegfr pages 9-13).
- IFITM3 regulation: SCAMP3 stabilizes IFITM3 without altering its ubiquitination, with statistically supported effects (n=3; P<0.05) and altered endosome→Golgi transport measured by CTXB uptake and flow cytometry (2016; preprint/unknown venue) (radic2016anovelrolea pages 88-97, radic2016anovelrole pages 88-97).
- Enterovirus replication: SCAMP3 KD/KO decreases EV-A71 RNA synthesis, viral proteins, and viral growth; reduces colocalization of PI4KIIIβ and PI4P with 3A (2021-09; Microbiol Spectrum; https://doi.org/10.1128/spectrum.00475-21) (lu2021secretorycarriermembrane pages 10-11).

7) Current applications and real-world implementations
- EV vaccine platform: SCAMP3 is required for budding of WW domain–activated EVs that present viral membrane antigens; immunization using WAEVs displaying influenza or HIV membrane proteins elicited neutralizing antibodies and conferred protection in mice (platform concept and mechanism; SCAMP3 requirement demonstrated in cells) (2023-01; Sci Adv; https://doi.org/10.1126/sciadv.ade2708) (choi2023displayinganddelivering pages 2-3).
- Oncology: SCAMP3’s modulation of EGFR fate and signaling positions it as a potential biomarker and functional target in EGFR‑driven tumors; in lung adenocarcinoma, SCAMP3 acts as a tumor suppressor via promoting EGFR degradation (2021-04; Oncogene; https://doi.org/10.1038/s41388-021-01764-y) and in TNBC, its expression correlates with aggressive phenotypes and worse outcomes (2022-06; Cancers; https://doi.org/10.3390/cancers14112807) (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10, acevedodiaz2022scamp3regulatesegfr pages 7-9, acevedodiaz2022scamp3regulatesegfr pages 19-21, acevedodiaz2022scamp3regulatesegfr pages 9-13).
- Antiviral strategies: SCAMP3’s roles in IFITM3 stabilization and enterovirus replication complexes suggest it as a node for modulating host–virus interactions (2016; 2021-09; https://doi.org/10.1128/spectrum.00475-21) (radic2016anovelrolea pages 88-97, radic2016anovelrole pages 88-97, lu2021secretorycarriermembrane pages 10-11).

8) Expert perspective and synthesis
- The preponderance of mechanistic data supports SCAMP3 as a multi-modal endosomal membrane organizer that bridges ESCRT entry points (via PSAP–TSG101 and HRS) with receptor fate decisions and vesicle biogenesis. PTMs act as switches: ubiquitylation state and EGFR‑driven phosphorylation at Y86 appear to bias SCAMP3 toward ILV sorting and degradation of EGFR, thereby constraining signaling. Conversely, under some conditions SCAMP3 can promote recycling; differences likely reflect cell type, ligand dose/time, and SCAMP3 modification status (2009 vs 2012 findings; inferential reconciliation) (aoh2009scamp3negativelyregulates pages 1-2, falguieres2012regulationofthe pages 7-9, radic2016anovelrolea pages 44-49). The 2023 EV study elevates SCAMP3 from a trafficking regulator to an indispensable biogenesis factor for a designer EV platform, showcasing translational relevance (choi2023displayinganddelivering pages 2-3). In cancer, the strongest experimental evidence indicates a tumor-suppressive role in EGFR‑mutant lung adenocarcinoma via Y86‑dependent degradation of EGFR, while in TNBC SCAMP3 aligns with aggressive traits; these contrasts emphasize context-specific signaling ecosystems (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10, acevedodiaz2022scamp3regulatesegfr pages 7-9, acevedodiaz2022scamp3regulatesegfr pages 19-21, acevedodiaz2022scamp3regulatesegfr pages 9-13).

Embedded summary table of key evidence
| Topic | Key finding/claim | System/model | Quantitative/stat info | Year | Source (journal) | DOI/URL | Citation ID |
|---|---|---|---|---|---|---|---|
| Identity / family / localization | SCAMP3 is a tetraspanning SCAMP family membrane protein with N-terminal NPF repeats; localizes to Golgi, early endosomes and a subset of late endosomes (~30% of late endosomes) | BHK / HeLa cells; IF, EM, proteomics | ~30% of late endosomes contain SCAMP3 (quantified by image analysis) | 2012 | Traffic | https://doi.org/10.1111/j.1600-0854.2011.01291.x | (falguieres2012regulationofthe pages 1-2) |
| ESCRT interactions, PY/PSAP motifs & ubiquitination | SCAMP3 is multi-monoubiquitylated; contains PY (PPAY) motif binding Nedd4-family E3s and PSAP motif that binds Tsg101; modulates EGFR recycling vs degradation | HeLa cells; RNAi, overexpression, mutagenesis, IP, EM | RNAi accelerates EGFR degradation; overexpression enhances recycling; requires ubiquitylatable lysines and intact PY/PSAP motifs | 2009 | Molecular Biology of the Cell | https://doi.org/10.1091/mbc.e08-09-0894 | (aoh2009scamp3negativelyregulates pages 1-2) |
| Role in MVB / ILV biogenesis & EGFR sorting | SCAMP3 required for ILV formation and EGF-driven MVB biogenesis; regulates sorting of EGFR into intralumenal vesicles and lysosomal targeting | HeLa / BHK; EM, invagination assays, stereology | Knockdown reduces ILV formation (stereological analysis ≈3000 μm² cytoplasm analyzed); effect significant (p<0.0001); impairs EGFR incorporation/degradation | 2012 | Traffic | https://doi.org/10.1111/j.1600-0854.2011.01291.x | (falguieres2012regulationofthe pages 7-9) |
| EGFR phosphorylation (Y86) & tumor-suppressor role | SCAMP3 is phosphorylated at Y86 by activated/mutant EGFR; Y86 phosphorylation required for SCAMP3-promoted EGFR degradation and tumor-suppressive phenotypes (WT rescues, Y86F does not) | Lung adenocarcinoma lines; SILAC phosphoproteomics, mutagenesis, xenografts | Multinucleation counts reported (control n=1576; SCAMP3-KD n=1132; rescue n=1283; Y86F n=1041); SCAMP3-KD delays EGFR degradation and increases xenograft growth | 2021 | Oncogene | https://doi.org/10.1038/s41388-021-01764-y | (venugopalan2021scamp3isa pages 10-12) |
| TNBC: EGFR trafficking, signaling & in vivo effects | SCAMP3 regulates EGFR internalization/redistribution and degradation, modulating AKT/ERK/STAT3; SCAMP3 loss reduces proliferation, migration, tumorsphere formation; xenografts show delayed early tumor growth; high SCAMP3 linked to worse RFS/DMFS (TCGA) | TNBC cell lines (MDA‑MB‑231, SUM‑149); SCAMP3 KO, orthotopic xenografts, TCGA analysis | Reduced proliferation at 72 h after EGF; early delay in tumor proliferation (week 1); association with decreased RFS/DMFS in patient data | 2022 | Cancers | https://doi.org/10.3390/cancers14112807 | (acevedodiaz2022scamp3regulatesegfr pages 7-9) |
| EV budding via WW–PPAY & PSAP–TSG101 dependency | SCAMP3 is essential for WW domain–activated extracellular vesicle (WAEV) budding; PPAY motif required for WW interaction; PSAP links to TSG101/ESCRT-I | Cell lines; CRISPR KO, NanoSight, proteomics, mutant re-expression | SCAMP3-KO: significant reduction in EV number (NanoSight) and near-complete loss of WAEV budding; WT re-expression restores budding, PPAA mutant fails to rescue | 2023 | Science Advances | https://doi.org/10.1126/sciadv.ade2708 | (choi2023displayinganddelivering pages 2-3) |
| Innate immunity: IFITM3 stabilization & trafficking | SCAMP3 stabilizes IFITM3 by reducing lysosomal degradation and alters endosome→Golgi retrograde transport; SCAMP3 physically interacts with IFITM3 but does not change IFITM3 ubiquitination | Cell-based assays; shRNA, inducible expression, co‑IP/MS, confocal, flow cytometry | Effects reproducible (n=3; s.d.; P<0.05 reported); IFITM3 ubiquitination pattern unchanged | 2016 | (unknown) | N/A | (radic2016anovelrolea pages 88-97) |
| Viral replication: EV‑A71 3A interaction & PI4KIIIβ/PI4P complex | SCAMP3 associates with enterovirus 3A, PI4KIIIβ and PI4P at replication sites and positively regulates viral RNA/protein synthesis and viral growth | EV‑A71 and CVB3 infection in cultured cells; IP + LC‑MS/MS; SCAMP3 KD/KO | SCAMP3 KD/KO decreases viral RNA synthesis, viral protein levels and viral growth; reduces PI4KIIIβ/PI4P colocalization with 3A | 2021 | Microbiology Spectrum | https://doi.org/10.1128/spectrum.00475-21 | (lu2021secretorycarriermembrane pages 10-11) |

Table: A compact table of primary findings on human SCAMP3 (UniProt O14828), listing mechanisms, systems, key quantitative results and source citations to facilitate rapid review and reference.

References (with URLs and dates)
- Aoh QL et al. SCAMP3 negatively regulates EGFR degradation and promotes receptor recycling. Mol Biol Cell. 2009-03. https://doi.org/10.1091/mbc.e08-09-0894 (aoh2009scamp3negativelyregulates pages 1-2)
- Falguières T et al. Regulation of the MVB Pathway by SCAMP3. Traffic. 2012-01. https://doi.org/10.1111/j.1600-0854.2011.01291.x (falguieres2012regulationofthe pages 1-2, falguieres2012regulationofthe pages 10-11, falguieres2012regulationofthe pages 7-9)
- Venugopalan A et al. SCAMP3 is a mutant EGFR phosphorylation target and a tumor suppressor in lung adenocarcinoma. Oncogene. 2021-04. https://doi.org/10.1038/s41388-021-01764-y (venugopalan2021scamp3isa pages 10-12, venugopalan2021scamp3isa pages 7-10, venugopalan2021scamp3isa pages 1-2)
- Acevedo-Díaz A et al. SCAMP3 regulates EGFR and promotes proliferation and migration of TNBC cells. Cancers. 2022-06. https://doi.org/10.3390/cancers14112807 (acevedodiaz2022scamp3regulatesegfr pages 7-9, acevedodiaz2022scamp3regulatesegfr pages 1-2, acevedodiaz2022scamp3regulatesegfr pages 19-21, acevedodiaz2022scamp3regulatesegfr pages 9-13)
- Choi S et al. Displaying and delivering viral membrane antigens via WW domain–activated extracellular vesicles. Sci Adv. 2023-01. https://doi.org/10.1126/sciadv.ade2708 (choi2023displayinganddelivering pages 2-3)
- Lu J‑Y et al. SCAMP3 interacts with enterovirus 3A and participates in viral replication. Microbiol Spectr. 2021-09. https://doi.org/10.1128/spectrum.00475-21 (lu2021secretorycarriermembrane pages 10-11)
- Radic V. A novel role for SCAMP3 as an innate immune factor. 2016. (repository/unknown); SCAMP3 stabilizes IFITM3 and alters retrograde transport (radic2016anovelrolea pages 88-97, radic2016anovelrole pages 88-97)

Compliance with identity checks
- Gene symbol and UniProt accession match the requested target: SCAMP3, UniProt O14828, human. Multiple sources explicitly refer to human SCAMP3 and its roles in human cells (Mol Biol Cell 2009; Traffic 2012; Oncogene 2021; Sci Adv 2023) (aoh2009scamp3negativelyregulates pages 1-2, falguieres2012regulationofthe pages 7-9, venugopalan2021scamp3isa pages 10-12, choi2023displayinganddelivering pages 2-3).
- Protein family/domains: Findings align with SCAMP family membership and tetraspanning topology; functional motifs (PPAY, PSAP) and ESCRT/WW-domain interactions are supported (aoh2009scamp3negativelyregulates pages 1-2, choi2023displayinganddelivering pages 2-3).

Limitations
- Some innate immunity data derive from a dissertation/unknown journal; mechanistic claims are supported by experimental assays but warrant independent primary validation (radic2016anovelrolea pages 88-97, radic2016anovelrole pages 88-97).

References

(falguieres2012regulationofthe pages 1-2): Thomas Falguières, David Castle, and Jean Gruenberg. Regulation of the mvb pathway by scamp3. Traffic, 13:131-142, Jan 2012. URL: https://doi.org/10.1111/j.1600-0854.2011.01291.x, doi:10.1111/j.1600-0854.2011.01291.x. This article has 48 citations and is from a peer-reviewed journal.
(aoh2009scamp3negativelyregulates pages 1-2): Quyen L. Aoh, Anna M. Castle, Charles H. Hubbard, Osamu Katsumata, and J. David Castle. Scamp3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling. Molecular biology of the cell, 20 6:1816-32, Mar 2009. URL: https://doi.org/10.1091/mbc.e08-09-0894, doi:10.1091/mbc.e08-09-0894. This article has 77 citations and is from a domain leading peer-reviewed journal.
(radic2016anovelrolea pages 44-49): V Radic. A novel role for scamp3 as an innate immune factor. Unknown journal, 2016.
(falguieres2012regulationofthe pages 10-11): Thomas Falguières, David Castle, and Jean Gruenberg. Regulation of the mvb pathway by scamp3. Traffic, 13:131-142, Jan 2012. URL: https://doi.org/10.1111/j.1600-0854.2011.01291.x, doi:10.1111/j.1600-0854.2011.01291.x. This article has 48 citations and is from a peer-reviewed journal.
(falguieres2012regulationofthe pages 7-9): Thomas Falguières, David Castle, and Jean Gruenberg. Regulation of the mvb pathway by scamp3. Traffic, 13:131-142, Jan 2012. URL: https://doi.org/10.1111/j.1600-0854.2011.01291.x, doi:10.1111/j.1600-0854.2011.01291.x. This article has 48 citations and is from a peer-reviewed journal.
(venugopalan2021scamp3isa pages 10-12): Abhilash Venugopalan, Matthew Lynberg, Constance M. Cultraro, Khoa Dang P. Nguyen, Xu Zhang, Maryam Waris, Noelle Dayal, Asebot Abebe, Tapan K. Maity, and Udayan Guha. Scamp3 is a mutant egfr phosphorylation target and a tumor suppressor in lung adenocarcinoma. Oncogene, 40:3331-3346, Apr 2021. URL: https://doi.org/10.1038/s41388-021-01764-y, doi:10.1038/s41388-021-01764-y. This article has 15 citations and is from a domain leading peer-reviewed journal.
(venugopalan2021scamp3isa pages 7-10): Abhilash Venugopalan, Matthew Lynberg, Constance M. Cultraro, Khoa Dang P. Nguyen, Xu Zhang, Maryam Waris, Noelle Dayal, Asebot Abebe, Tapan K. Maity, and Udayan Guha. Scamp3 is a mutant egfr phosphorylation target and a tumor suppressor in lung adenocarcinoma. Oncogene, 40:3331-3346, Apr 2021. URL: https://doi.org/10.1038/s41388-021-01764-y, doi:10.1038/s41388-021-01764-y. This article has 15 citations and is from a domain leading peer-reviewed journal.
(venugopalan2021scamp3isa pages 1-2): Abhilash Venugopalan, Matthew Lynberg, Constance M. Cultraro, Khoa Dang P. Nguyen, Xu Zhang, Maryam Waris, Noelle Dayal, Asebot Abebe, Tapan K. Maity, and Udayan Guha. Scamp3 is a mutant egfr phosphorylation target and a tumor suppressor in lung adenocarcinoma. Oncogene, 40:3331-3346, Apr 2021. URL: https://doi.org/10.1038/s41388-021-01764-y, doi:10.1038/s41388-021-01764-y. This article has 15 citations and is from a domain leading peer-reviewed journal.
(acevedodiaz2022scamp3regulatesegfr pages 9-13): Ariana Acevedo-Díaz, Beatriz M. Morales-Cabán, Astrid Zayas-Santiago, Michelle M. Martínez-Montemayor, and Ivette J. Suárez-Arroyo. Scamp3 regulates egfr and promotes proliferation and migration of triple-negative breast cancer cells through the modulation of akt, erk, and stat3 signaling pathways. Cancers, 14:2807, Jun 2022. URL: https://doi.org/10.3390/cancers14112807, doi:10.3390/cancers14112807. This article has 14 citations and is from a poor quality or predatory journal.
(choi2023displayinganddelivering pages 2-3): Sengjin Choi, Zhiping Yang, Qiyu Wang, Zhi Qiao, Maoyun Sun, Joshua Wiggins, Shi-Hua Xiang, and Quan Lu. Displaying and delivering viral membrane antigens via ww domain–activated extracellular vesicles. Science Advances, Jan 2023. URL: https://doi.org/10.1126/sciadv.ade2708, doi:10.1126/sciadv.ade2708. This article has 24 citations and is from a highest quality peer-reviewed journal.
(radic2016anovelrolea pages 88-97): V Radic. A novel role for scamp3 as an innate immune factor. Unknown journal, 2016.
(radic2016anovelrole pages 88-97): V Radic. A novel role for scamp3 as an innate immune factor. Unknown journal, 2016.
(lu2021secretorycarriermembrane pages 10-11): Jia-Ying Lu, Gary Brewer, Mei-Ling Li, Kai-Zhe Lin, Chien-Chih Huang, Li-Chen Yen, and Jing-Yi Lin. Secretory carrier membrane protein 3 interacts with 3a viral protein of enterovirus and participates in viral replication. Microbiology Spectrum, Sep 2021. URL: https://doi.org/10.1128/spectrum.00475-21, doi:10.1128/spectrum.00475-21. This article has 10 citations and is from a domain leading peer-reviewed journal.
(acevedodiaz2022scamp3regulatesegfr pages 7-9): Ariana Acevedo-Díaz, Beatriz M. Morales-Cabán, Astrid Zayas-Santiago, Michelle M. Martínez-Montemayor, and Ivette J. Suárez-Arroyo. Scamp3 regulates egfr and promotes proliferation and migration of triple-negative breast cancer cells through the modulation of akt, erk, and stat3 signaling pathways. Cancers, 14:2807, Jun 2022. URL: https://doi.org/10.3390/cancers14112807, doi:10.3390/cancers14112807. This article has 14 citations and is from a poor quality or predatory journal.
(acevedodiaz2022scamp3regulatesegfr pages 1-2): Ariana Acevedo-Díaz, Beatriz M. Morales-Cabán, Astrid Zayas-Santiago, Michelle M. Martínez-Montemayor, and Ivette J. Suárez-Arroyo. Scamp3 regulates egfr and promotes proliferation and migration of triple-negative breast cancer cells through the modulation of akt, erk, and stat3 signaling pathways. Cancers, 14:2807, Jun 2022. URL: https://doi.org/10.3390/cancers14112807, doi:10.3390/cancers14112807. This article has 14 citations and is from a poor quality or predatory journal.
(acevedodiaz2022scamp3regulatesegfr pages 19-21): Ariana Acevedo-Díaz, Beatriz M. Morales-Cabán, Astrid Zayas-Santiago, Michelle M. Martínez-Montemayor, and Ivette J. Suárez-Arroyo. Scamp3 regulates egfr and promotes proliferation and migration of triple-negative breast cancer cells through the modulation of akt, erk, and stat3 signaling pathways. Cancers, 14:2807, Jun 2022. URL: https://doi.org/10.3390/cancers14112807, doi:10.3390/cancers14112807. This article has 14 citations and is from a poor quality or predatory journal.

Citations

falguieres2012regulationofthe pages 1-2
falguieres2012regulationofthe pages 7-9
choi2023displayinganddelivering pages 2-3
lu2021secretorycarriermembrane pages 10-11
radic2016anovelrolea pages 88-97
radic2016anovelrolea pages 44-49
falguieres2012regulationofthe pages 10-11
radic2016anovelrole pages 88-97
https://doi.org/10.1111/j.1600-0854.2011.01291.x
https://doi.org/10.1091/mbc.e08-09-0894
https://doi.org/10.1038/s41388-021-01764-y
https://doi.org/10.1038/s41388-021-01764-y;
https://doi.org/10.3390/cancers14112807
https://doi.org/10.1091/mbc.e08-09-0894;
https://doi.org/10.1126/sciadv.ade2708
https://doi.org/10.1128/spectrum.00475-21
https://doi.org/10.1111/j.1600-0854.2011.01291.x,
https://doi.org/10.1091/mbc.e08-09-0894,
https://doi.org/10.1038/s41388-021-01764-y,
https://doi.org/10.3390/cancers14112807,
https://doi.org/10.1126/sciadv.ade2708,
https://doi.org/10.1128/spectrum.00475-21,

📄 View Raw YAML

id: O14828
gene_symbol: SCAMP3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SCAMP3 (Secretory carrier-associated membrane protein 3) is a
  tetraspanning integral membrane protein that functions as a key regulator of
  endosomal trafficking and multivesicular body (MVB) biogenesis. The protein
  contains an N-terminal cytoplasmic domain with functionally critical motifs
  including a PPAY motif that binds WW-domain E3 ubiquitin ligases (NEDD4
  family) and a PSAP motif that mediates interaction with the ESCRT-I component
  TSG101. SCAMP3 localizes to the Golgi apparatus, early endosomes, and a subset
  of late endosomes. It plays a central role in regulating epidermal growth
  factor receptor (EGFR) trafficking fate, balancing receptor recycling versus
  lysosomal degradation through ESCRT-dependent sorting into intralumenal
  vesicles. SCAMP3 is multi-monoubiquitinated and is itself phosphorylated by
  EGFR at Tyr86, which promotes EGFR-SCAMP3 interaction and EGFR degradation.
  SCAMP3 is essential for WW domain-activated extracellular vesicle (WAEV)
  budding, positioning it as a critical factor in exosome/EV biogenesis.
existing_annotations:
  - term:
      id: GO:0006887
      label: exocytosis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This IBA annotation derives from phylogenetic inference across
        the SCAMP family. While SCAMP3 is involved in vesicular trafficking
        pathways, the primary experimental evidence supports its role in
        endosomal sorting and MVB biogenesis rather than classical exocytosis.
        The original SCAMP1/2 literature focused on post-Golgi recycling
        carriers, but SCAMP3-specific studies emphasize EGFR trafficking and
        intralumenal vesicle formation (PMID:19158374).
      action: MODIFY
      reason: The term 'exocytosis' is too general and does not capture the
        specific role of SCAMP3. The deep research indicates SCAMP3 functions
        primarily in endosomal sorting, MVB biogenesis, and regulation of
        receptor recycling vs degradation rather than classical exocytosis. A
        more appropriate term would be 'post-Golgi vesicle-mediated transport'
        (which already exists as another annotation) or 'endosomal transport'.
      proposed_replacement_terms:
        - id: GO:0016197
          label: endosomal transport
      additional_reference_ids:
        - PMID:19158374
        - file:human/SCAMP3/SCAMP3-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: SCAMP3 negatively regulates epidermal growth factor
            receptor degradation and promotes receptor recycling
        - reference_id: file:human/SCAMP3/SCAMP3-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0032588
      label: trans-Golgi network membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This IBA annotation is consistent with experimental findings. The
        deep research indicates SCAMP3 localizes to the Golgi apparatus, and the
        original 1997 paper (PMID:9378760) showed SCAMPs have similar
        subcellular distributions including Golgi-associated compartments. The
        2012 Traffic paper confirmed SCAMP3 localization to Golgi and endosomal
        compartments.
      action: ACCEPT
      reason: The annotation accurately reflects SCAMP3 localization. Literature
        demonstrates SCAMP3 presence at Golgi and trans-Golgi network membranes
        consistent with its role in post-Golgi trafficking.
      supported_by:
        - reference_id: PMID:9378760
          supporting_text: Examination of the codistribution of the three forms
            within individual cells using double label immunofluorescence
            indicates extensive colocalization of SCAMP2 and SCAMP3 with
            endogenous SCAMP1
  - term:
      id: GO:0055038
      label: recycling endosome membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This IBA annotation is well-supported by experimental evidence.
        SCAMP3 promotes receptor recycling and localizes to endosomal
        compartments including recycling endosomes. The 2009 Mol Biol Cell paper
        demonstrated that SCAMP3 promotes EGFR recycling rather than degradation
        (PMID:19158374).
      action: ACCEPT
      reason: The annotation accurately reflects SCAMP3 localization and
        function. SCAMP3 functions as a recycling carrier and promotes receptor
        recycling from endosomal compartments back to the plasma membrane.
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: SCAMP3 negatively regulates epidermal growth factor
            receptor degradation and promotes receptor recycling
  - term:
      id: GO:0015031
      label: protein transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: This IEA annotation inferred from InterPro domain and UniProtKB
        keywords is accurate but very general. SCAMP3 is indeed involved in
        protein transport through its role in vesicular trafficking, EGFR
        sorting, and MVB pathway regulation.
      action: ACCEPT
      reason: The annotation is correct but represents a high-level term. More
        specific annotations like post-Golgi vesicle-mediated transport and
        endosomal transport better capture SCAMP3 function. However, this IEA
        annotation is not incorrect and provides appropriate coverage.
      supported_by:
        - reference_id: PMID:9378760
          supporting_text: The SCAMPs may largely function at the same sites
            during vesicular transport rather than in separate post-Golgi
            recycling pathways
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: This IEA annotation is correct. SCAMP3 is a tetraspanning
        integral membrane protein with four transmembrane helices (residues
        171-191, 197-217, 247-267, 277-297) according to UniProt annotation.
      action: ACCEPT
      reason: The annotation is accurate. SCAMP3 is clearly a membrane protein
        with four transmembrane domains. More specific membrane localizations
        (trans-Golgi network membrane, recycling endosome membrane) are captured
        in other annotations.
      supported_by:
        - reference_id: PMID:9378760
          supporting_text: SCAMPs are highly related products of distinct genes
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IPI
    original_reference_id: PMID:23418353
    review:
      summary: This IPI annotation is well-supported. SCAMP3 contains a PPAY
        motif that binds WW-domain E3 ubiquitin ligases including NEDD4 and
        NEDD4L. The UniProt entry confirms interactions with NEDD4, NEDD4L,
        TSG101, and RNF126. The cited paper (PMID:23418353) demonstrates SCAMP3
        interaction with RNF126 E3 ubiquitin ligase.
      action: ACCEPT
      reason: The annotation accurately reflects SCAMP3's molecular function.
        The PPAY motif mediates binding to WW-domain containing E3 ubiquitin
        ligases. This interaction is functionally important for SCAMP3's role in
        endosomal sorting and receptor trafficking.
      supported_by:
        - reference_id: PMID:23418353
          supporting_text: We also show that the depletion of Rabring7
            attenuates the degradation of MET and that both RNF126 and Rabring7
            regulate the sorting of CXCR4 from an early endocytic compartment
        - reference_id: PMID:19158374
          supporting_text: SCAMP3 is multimonoubiquitylated and is able to
            associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit
            Tsg101 via its PY and PSAP motifs, respectively
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: This HDA annotation from high-throughput proteomics is strongly
        supported by recent functional studies. The 2023 Science Advances paper
        demonstrated that SCAMP3 is essential for WW domain-activated
        extracellular vesicle (WAEV) budding. SCAMP3 knockout nearly abolishes
        EV production measured by NanoSight, and only wild-type (not PPAY
        mutant) SCAMP3 can rescue this phenotype.
      action: ACCEPT
      reason: The annotation is experimentally validated by multiple studies.
        SCAMP3 was identified in B-cell exosome proteomics and later shown to be
        functionally required for extracellular vesicle biogenesis through its
        PPAY-WW domain interactions.
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: We first analyzed the total proteome of highly
            purified B cell-derived exosomes using sensitive and accurate mass
            spectrometry (MS), and identified 539 proteins
  - term:
      id: GO:0006892
      label: post-Golgi vesicle-mediated transport
    evidence_type: TAS
    original_reference_id: PMID:9378760
    review:
      summary: This TAS annotation from the original SCAMP characterization
        paper is well-supported. The 1997 paper established that SCAMPs function
        in post-Golgi recycling pathways, and subsequent studies have confirmed
        SCAMP3's role in trafficking from Golgi through endosomal compartments.
      action: ACCEPT
      reason: The annotation accurately reflects a core function of SCAMP3. The
        protein functions in post-Golgi vesicular transport, mediating carrier
        function between Golgi, endosomal compartments, and plasma membrane.
      supported_by:
        - reference_id: PMID:9378760
          supporting_text: These findings suggest that the SCAMPs may largely
            function at the same sites during vesicular transport rather than in
            separate post-Golgi recycling pathways
  - term:
      id: GO:0070676
      label: intralumenal vesicle formation
    evidence_type: IDA
    original_reference_id: file:human/SCAMP3/SCAMP3-deep-research-falcon.md
    review:
      summary: NEW annotation supported by direct experimental evidence. The
        2012 Traffic paper demonstrated that SCAMP3 knockdown significantly
        reduces intralumenal vesicle (ILV) formation in multivesicular bodies
        (stereological analysis, p<0.0001). SCAMP3 is required for cargo sorting
        into ILVs and MVB biogenesis.
      action: NEW
      reason: Strong experimental evidence supports this annotation. SCAMP3 is
        required for ILV formation through its interaction with ESCRT machinery
        via the PSAP-TSG101 and PPAY-WW domain interactions.
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: SCAMP3, its modification with ubiquitin, and its
            interactions with ESCRTs coordinately regulate endosomal pathways
            and affect the efficiency of receptor down-regulation
  - term:
      id: GO:0005770
      label: late endosome
    evidence_type: IDA
    original_reference_id: file:human/SCAMP3/SCAMP3-deep-research-falcon.md
    review:
      summary: NEW annotation supported by experimental evidence. The 2012
        Traffic paper demonstrated that approximately 30% of late endosomes
        contain SCAMP3 based on quantitative image analysis. SCAMP3 localizes to
        a subset of late endosomes/MVBs.
      action: NEW
      reason: Direct evidence from immunofluorescence and EM studies shows
        SCAMP3 localization to late endosomal compartments where it functions in
        cargo sorting and ILV formation.
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: SCAMP3 depletion appeared to sustain the incidence of
            EGFR-containing MVBs detected by immunoelectron microscopy
  - term:
      id: GO:0001881
      label: receptor recycling
    evidence_type: IMP
    original_reference_id: PMID:19158374
    review:
      summary: NEW annotation supported by experimental evidence. The 2009 Mol
        Biol Cell paper demonstrated that SCAMP3 promotes EGFR recycling. SCAMP3
        overexpression enhanced EGFR recycling while knockdown accelerated
        degradation and impaired recycling.
      action: NEW
      reason: Strong experimental evidence from mutant analysis shows SCAMP3
        functions in promoting receptor recycling, balancing recycling vs
        degradation fate.
      additional_reference_ids:
        - PMID:19158374
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: Depletion of SCAMP3 in HeLa cells by inhibitory RNA
            accelerated degradation of EGFR and EGF while inhibiting recycling
  - term:
      id: GO:0032585
      label: multivesicular body membrane
    evidence_type: IDA
    original_reference_id: file:human/SCAMP3/SCAMP3-deep-research-falcon.md
    review:
      summary: NEW annotation supported by experimental evidence. SCAMP3
        localizes to and functions at MVB membranes, where it is required for
        ILV formation and cargo sorting.
      action: NEW
      reason: SCAMP3 localization to MVB membranes is demonstrated through its
        role in MVB biogenesis and ESCRT-dependent sorting.
      supported_by:
        - reference_id: PMID:19158374
          supporting_text: SCAMP3 depletion appeared to sustain the incidence of
            EGFR-containing MVBs detected by immunoelectron microscopy
references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential
      functional implications for exosome biogenesis.
    findings:
      - statement: SCAMP3 identified in B-cell exosome proteome
        supporting_text: We first analyzed the total proteome of highly purified
          B cell-derived exosomes using sensitive and accurate mass spectrometry
          (MS), and identified 539 proteins
  - id: PMID:23418353
    title: The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal
      sorting of the epidermal growth factor receptor.
    findings:
      - statement: RNF126 and Rabring7 regulate EGFR endosomal sorting
        supporting_text: RNF126 and Rabring7 regulate endosomal sorting of the
          epidermal growth factor receptor
  - id: PMID:9378760
    title: Three mammalian SCAMPs (secretory carrier membrane proteins) are
      highly related products of distinct genes having similar subcellular
      distributions.
    findings:
      - statement: SCAMP3 characterized as member of SCAMP family
        supporting_text: Three mammalian SCAMPs (secretory carrier membrane
          proteins) are highly related products of distinct genes having similar
          subcellular distributions
      - statement: SCAMPs colocalize and function in post-Golgi recycling
          pathways
        supporting_text: These findings suggest that the SCAMPs may largely
          function at the same sites during vesicular transport rather than in
          separate post-Golgi recycling pathways
  - id: PMID:19158374
    title: SCAMP3 negatively regulates epidermal growth factor receptor
      degradation and promotes receptor recycling.
    findings:
      - statement: SCAMP3 contains PPAY motif binding NEDD4 family E3 ligases
        supporting_text: SCAMP3 is multimonoubiquitylated and is able to
          associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit
          Tsg101 via its PY and PSAP motifs, respectively
      - statement: SCAMP3 is multi-monoubiquitinated
        supporting_text: SCAMP3 is multimonoubiquitylated
      - statement: SCAMP3 promotes EGFR recycling over degradation
        supporting_text: Depletion of SCAMP3 in HeLa cells by inhibitory RNA
          accelerated degradation of EGFR and EGF while inhibiting recycling
      - statement: SCAMP3 interacts with NEDD4, NEDD4L, and TSG101
        supporting_text: SCAMP3 is multimonoubiquitylated and is able to
          associate with Nedd4 HECT ubiquitin ligases and the ESCRT-I subunit
          Tsg101 via its PY and PSAP motifs, respectively
  - id: file:human/SCAMP3/SCAMP3-deep-research-falcon.md
    title: Deep research on SCAMP3 function
    findings:
      - statement: SCAMP3 required for ILV formation in MVBs based on 2012
          Traffic paper
      - statement: SCAMP3 localizes to late endosomes based on
          immunofluorescence studies
core_functions:
  - description: SCAMP3 functions as a multi-modal regulator of endosomal
      trafficking, controlling the fate of cargo proteins including EGFR between
      recycling and lysosomal degradation pathways through interactions with
      ESCRT machinery.
    molecular_function:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    directly_involved_in:
      - id: GO:0016197
        label: endosomal transport
      - id: GO:0070676
        label: intralumenal vesicle formation
    locations:
      - id: GO:0055038
        label: recycling endosome membrane
      - id: GO:0032585
        label: multivesicular body membrane
      - id: GO:0032588
        label: trans-Golgi network membrane
proposed_new_terms: []
suggested_questions:
  - question: How does SCAMP3 ubiquitination state regulate the balance between
      receptor recycling and degradation?
  - question: What is the precise mechanism by which SCAMP3 coordinates with
      ESCRT-0 (HRS) in addition to ESCRT-I (TSG101)?
suggested_experiments:
  - description: Structure-function analysis of SCAMP3 using site-directed
      mutagenesis of the ubiquitination sites to determine how ubiquitination
      state affects recycling vs degradation outcomes. This could resolve the
      apparent discrepancy between SCAMP3's role in promoting recycling versus
      driving lysosomal degradation.

Gene Description

Existing Annotations Review

Core Functions

SCAMP3 functions as a multi-modal regulator of endosomal trafficking, controlling the fate of cargo proteins including EGFR between recycling and lysosomal degradation pathways through interactions with ESCRT machinery.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Citations

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