Affinage

SCAMP3

Secretory carrier-associated membrane protein 3 · UniProt O14828

Round 2 corrected
Length
347 aa
Mass
38.3 kDa
Annotated
2026-04-28
45 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCAMP3 is a multi-ubiquitylated transmembrane protein of post-Golgi vesicles and early endosomes that orchestrates receptor trafficking, multivesicular body (MVB) biogenesis, and regulated secretory granule formation across multiple cell types. It interacts with ESCRT machinery (Tsg101 via its PSAP motif, Hrs) and Nedd4 ubiquitin ligases (via its PY motif) to regulate EGFR sorting into MVBs and intralumenal vesicle formation, and is itself phosphorylated at Y86 by EGFR, a modification required for its pro-degradative and tumor-suppressive functions in lung adenocarcinoma (PMID:9658162, PMID:19158374, PMID:21951651, PMID:33850265). Beyond EGFR trafficking, SCAMP3 is essential for neutrophil granule biogenesis and degranulation, regulates insulin granule content and secretion in pancreatic β-cells, and recruits the lipid transfer protein BLTP2 to ER–MVB contact sites in a Rab5-dependent manner to supply phospholipid precursors for ILV/exosome formation (PMID:41187789, PMID:39320956). In cancer contexts, SCAMP3 modulates ERK/AKT/STAT3 signaling downstream of EGFR and influences autophagic flux, with its loss disrupting mTORC1 signaling and SQSTM1/p62 turnover (PMID:35681787, PMID:41096842).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Establishing that SCAMP3 is a direct EGFR substrate answered the question of whether secretory carrier-associated membrane proteins participate in receptor tyrosine kinase signaling, linking SCAMP3 to EGF-stimulated trafficking.

    Evidence Co-immunoprecipitation, in vitro kinase assay with recombinant EGFR, vanadate treatment, and PTP1B dephosphorylation in murine fibroblasts overexpressing EGFR

    PMID:9658162

    Open questions at the time
    • Specific phosphorylation site not mapped in this study
    • Functional consequence of phosphorylation on trafficking not tested
  2. 2009 High

    Demonstrating that SCAMP3 interacts with ESCRT components (Tsg101, Hrs) and Nedd4 via defined motifs, and that its depletion accelerates EGFR degradation while inhibiting recycling, established SCAMP3 as a regulator of endosomal receptor sorting acting in parallel with the canonical ESCRT pathway.

    Evidence siRNA knockdown, domain mutagenesis (PY, PSAP, lysine mutants), co-immunoprecipitation, immunoelectron microscopy, and quantitative degradation/recycling assays in HeLa cells

    PMID:19158374

    Open questions at the time
    • Whether SCAMP3 acts catalytically or as a scaffold is unclear
    • Structural basis of SCAMP3-ESCRT interactions not resolved
  3. 2011 High

    In vitro reconstitution of MVB biogenesis showed SCAMP3 promotes intralumenal vesicle formation, moving the protein's role beyond receptor recycling to active participation in MVB/ILV generation.

    Evidence Cell-free MVB biogenesis assay combined with siRNA knockdown and EGFR sorting readouts

    PMID:21951651

    Open questions at the time
    • Lipid requirements for SCAMP3-dependent ILV formation not defined
    • Mechanism by which SCAMP3 promotes membrane budding not established
  4. 2021 High

    Identification of Y86 as the critical EGFR-dependent phosphorylation site on SCAMP3, and demonstration that Y86F mutation abolishes tumor-suppressive function in lung adenocarcinoma xenografts, established the mechanistic link between EGFR phosphorylation and SCAMP3's pro-degradative activity.

    Evidence Quantitative phosphoproteomics, Y86F mutagenesis rescue, co-immunoprecipitation, and xenograft models

    PMID:33850265

    Open questions at the time
    • Whether Y86 phosphorylation alters SCAMP3's affinity for ESCRT components specifically is untested
    • Relevance of Y86 outside lung adenocarcinoma not explored
  5. 2022 Medium

    CRISPR knockout of SCAMP3 in triple-negative breast cancer cells revealed that SCAMP3 is required for efficient EGFR degradation and modulates AKT/ERK/STAT3 signaling, extending its oncogenic relevance beyond lung to breast cancer and clarifying its context-dependent pro- versus anti-tumorigenic roles.

    Evidence CRISPR knockout, EGFR internalization/degradation assays, immunoblots, xenograft models in TNBC cells

    PMID:35681787

    Open questions at the time
    • Direction of SCAMP3's role (tumor-suppressive vs. oncogenic) appears context-dependent and unresolved
    • Single-lab study without independent replication
  6. 2024 Medium

    Identification of SCAMP3 as an insulin secretory granule-associated protein that controls insulin content and secretion established a role for SCAMP3 in regulated exocytosis beyond the endolysosomal system.

    Evidence Protein correlation profiling mass spectrometry on isolated ISGs from MIN6 and human β-cells, confocal colocalization, siRNA knockdown with insulin secretion assay in INS-1 cells

    PMID:39320956

    Open questions at the time
    • Mechanism by which SCAMP3 maintains insulin granule content unknown
    • Not yet confirmed in primary human islets
  7. 2025 High

    Knockout studies in mammalian neutrophil-like cells and zebrafish demonstrated that SCAMP3 is essential for formation and content of all three neutrophil granule classes and for degranulation-dependent bacterial killing, broadening its role to innate immune defense.

    Evidence Scamp3 KO in Hoxb8 cells and zebrafish, mass spectrometry, degranulation assay, E. coli killing assay, in vivo zebrafish infection

    PMID:41187789

    Open questions at the time
    • Whether SCAMP3 acts during granule biogenesis at the TGN or in granule maturation is unresolved
    • Molecular mechanism linking SCAMP3 to granule protein retention not defined
  8. 2025 Medium

    Phosphoproteomics of SCAMP3-KO TNBC cells under ERK inhibition revealed that SCAMP3 sustains residual ERK activity and mTORC1 signaling and that its loss disrupts autophagic flux, mechanistically connecting SCAMP3 to MAPK feedback regulation and autophagy.

    Evidence TMT-based phosphoproteomics of WT vs SCAMP3-KO MDA-MB-231 cells ± EGF ± MK-8353, immunoblotting

    PMID:41096842

    Open questions at the time
    • Whether SCAMP3 directly affects ERK feedback or acts indirectly via receptor trafficking is unclear
    • Autophagy disruption could be secondary to endosomal dysfunction
  9. 2025 Medium

    SCAMP3 was shown to recruit the lipid transfer protein BLTP2 to ER–MVB contact sites in a Rab5-dependent manner, with NEDD4-mediated ubiquitination of SCAMP3 antagonizing this recruitment, providing a mechanistic explanation for how SCAMP3 supplies phospholipid precursors (PG, BMP/LBPA) for ILV/exosome biogenesis.

    Evidence (preprint) Co-immunoprecipitation, proximity ligation, BLTP2 KO, lipidomics, exosome quantification, Rab5 dominant-negative experiments

    PMID:bio_10.1101_2025.04.17.649455

    Open questions at the time
    • Not yet peer-reviewed
    • Whether SCAMP3–BLTP2 axis operates in non-endosomal granule contexts is untested
    • Direct lipid transfer activity of the SCAMP3–BLTP2 complex not reconstituted in vitro

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for SCAMP3's interactions with ESCRT components and BLTP2, the molecular basis for its context-dependent pro- versus anti-tumorigenic roles across cancer types, and whether its granule biogenesis function in neutrophils and β-cells shares a common trafficking mechanism with its endosomal role.
  • No atomic-resolution structure of SCAMP3 or its complexes
  • No in vivo mammalian knockout phenotype reported
  • Unified model reconciling EGFR recycling/degradation roles with granule biogenesis roles is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 3 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
BLTP2EGFREPS8HRSNEDD4TSG101

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SCAMP1 and SCAMP3 are selectively tyrosine-phosphorylated in EGF-stimulated murine fibroblasts overexpressing EGFR. SCAMP3 is phosphorylated by EGFR in vitro, and EGF induces SCAMP3-EGFR association detectable by co-immunoprecipitation. Vanadate-induced phosphorylation causes partial accumulation of SCAMP3 at the cell surface, and phosphorylation is reversible by PTP1B in vitro. Co-immunoprecipitation, in vitro kinase assay with recombinant EGFR, vanadate treatment, PTP1B dephosphorylation assay, immunofluorescence Molecular biology of the cell High 9658162
2009 SCAMP3 localizes in part to early endosomes and negatively regulates EGFR degradation while promoting its recycling. SCAMP3 is multi-monoubiquitylated and interacts with Nedd4 HECT ubiquitin ligases via its PY motif and with ESCRT-I subunit Tsg101 via its PSAP motif, and also associates with ESCRT-0 subunit Hrs. Depletion of SCAMP3 accelerates EGFR and EGF degradation and inhibits recycling; overexpression enhances recycling unless ubiquitylatable lysines or PY/PSAP motifs are mutated. Dual depletion experiments indicate SCAMP3 acts in parallel with ESCRTs to regulate receptor degradation. siRNA knockdown, overexpression with domain mutants, co-immunoprecipitation, immunoelectron microscopy, quantitative degradation and recycling assays in HeLa cells Molecular biology of the cell High 19158374
2009 SCAMP3 accumulates on the trans-Golgi network in uninfected cells and contributes to maintenance of Salmonella-containing vacuoles (SCVs) in the Golgi region of HeLa cells, as revealed by siRNA screen. During Salmonella infection, SCAMP3 marks tubular structures induced by bacterial effectors that overlap with but are distinct from Salmonella-induced filaments (SIFs), suggesting SCAMP3 marks a post-Golgi trafficking pathway manipulated by Salmonella. siRNA screen, immunofluorescence microscopy in infected HeLa cells Cellular microbiology Medium 19438519
2011 SCAMP3 plays a positive role in the biogenesis of multivesicular endosomes (MVBs) by promoting EGF receptor sorting into MVBs and formation of intralumenal vesicles (ILVs) within them. This was demonstrated in a cell-free in vitro MVB biogenesis assay, and SCAMP3 was shown to control EGF receptor targeting to lysosomes and to regulate EGF-dependent MVB biogenesis. In vitro MVB biogenesis assay, siRNA knockdown, EGFR sorting assay Traffic High 21951651
2019 SCAMP3 participates in a feed-forward regulatory loop with miR-27a/b-3p and PPARG during adipogenesis. miR-27a/b-3p suppresses both PPARG and SCAMP3 independently; PPARG knockdown downregulates SCAMP3 at late adipogenesis; SCAMP3 knockdown increases PPARG expression at early differentiation and upregulates adipocyte markers ADIPOQ and FABP4, indicating an anti-adipogenic role for SCAMP3. miRNA overexpression, siRNA knockdown of PPARG and SCAMP3, RT-qPCR, adipogenesis differentiation assays Scientific reports Medium 31554889
2021 Mutant EGFR (directly or indirectly) phosphorylates SCAMP3 at Y86, and this phosphorylation increases SCAMP3 interaction with both wild-type and mutant EGFRs. SCAMP3 functions as a tumor suppressor in lung adenocarcinoma by promoting EGFR degradation and attenuating MAP kinase signaling. SCAMP3 knockdown increases lung adenocarcinoma cell survival, xenograft tumor growth, and multinucleated cells; re-expression of wild-type SCAMP3 but not SCAMP3-Y86F rescues these phenotypes, demonstrating that Y86 phosphorylation is critical for function. Quantitative phosphoproteomics, site-directed mutagenesis (Y86F), co-immunoprecipitation, siRNA knockdown, xenograft mouse model, EGFR degradation assay Oncogene High 33850265
2022 SCAMP3 colocalizes with EGFR and redistributes it from cytoplasm to the perinucleus as shown by internalization assay. SCAMP3 knockout in TNBC cells decreases EGFR degradation and modulates AKT, ERK, and STAT3 signaling pathways. SCAMP3 loss reduces proliferation, colony/tumorsphere formation, migration, and invasion, and delays tumor growth in xenograft models. SCAMP3 knockout (CRISPR), EGFR internalization/colocalization assay, immunoblots, EGFR degradation assay, xenograft mouse model Cancers Medium 35681787
2023 SCAMP3 promotes breast cancer cell growth, stemness, and metastasis by modulating the c-MYC–β-Catenin–SQSTM1 oncogenic axis. SCAMP3 depletion inhibits β-Catenin, c-MYC, and SQSTM1 expression, promotes autophagy and cellular senescence, and reduces stemness markers CD44 and OCT4A; SCAMP3 overexpression has the opposite effects and enhances in vivo tumor growth in xenograft models. siRNA knockdown, overexpression, immunoblotting, in vivo xenograft, flow cytometry, colony and tumorsphere assays Cellular signalling Medium 36627007
2024 SCAMP3/Scamp3 is identified as a novel insulin secretory granule (ISG)-associated protein in MIN6 and human β-cells by mass spectrometry-based proteomics with protein correlation profiling. Scamp3 knockdown in INS-1 cells reduces insulin content and causes dysfunctional insulin secretion, establishing a functional role for SCAMP3 in regulating insulin granule biology. Optimized ISG isolation, mass spectrometry proteomics, confocal colocalization, siRNA knockdown in INS-1 cells, insulin secretion assay Diabetes Medium 39320956
2025 SCAMP3 and EPS8 cooperatively maintain EGFR stability and signaling in prostate cancer cells. EGF stimulation promotes formation of a protein complex containing EGFR, SCAMP3, EPS8, and AR-V7 as detected by co-immunoprecipitation. Knockdown of SCAMP3 or EPS8 reduces EGFR expression and attenuates STAT3, AKT, and ERK activation; overexpression of either protein increases EGFR levels and enhances downstream signaling, demonstrating functional interdependence. Co-immunoprecipitation, Western blotting, shRNA knockdown, pcDNA overexpression, EGF stimulation assays in LNCaP and enzalutamide-resistant LNCaP-Enz cells Cancer genomics & proteomics Medium 41151858
2025 SCAMP3 is essential for proper neutrophil granule formation and degranulation. Scamp3 knockout in Hoxb8 cells and in zebrafish results in significant reduction of primary, secondary, and tertiary granule proteins (by mass spectrometry and Western blot), reduced overall granularity, impaired degranulation, and compromised killing of E. coli in vitro. Neutrophil migration toward infection sites is unaffected, indicating a granule-specific rather than chemotaxis role. Scamp3 knockout (Hoxb8 cell system and zebrafish), mass spectrometry, Western blotting, bacterial killing assay, degranulation assay, in vivo zebrafish infection model Journal of leukocyte biology High 41187789
2025 SCAMP3 recruits the ER membrane lipid transfer protein BLTP2 to ER–MVB membrane contact sites in a Rab5-dependent manner, facilitating lysobisphosphatidic acid (BMP/LBPA) precursor phosphatidylglycerol transfer to MVBs for ILV/exosome biogenesis. NEDD4-mediated ubiquitination of SCAMP3 inhibits this recruitment. BLTP2 depletion selectively reduces cone-shaped phospholipids (BMP, PG) within endosomes and impairs ILV/exosome formation. Co-immunoprecipitation, proximity ligation/colocalization, BLTP2 knockout, lipidomics, exosome quantification, Rab5 dominant-negative experiments bioRxivpreprint Medium bio_10.1101_2025.04.17.649455
2025 SCAMP3 loss (SC3KO) abolishes residual ERK activity under ERK1/2 inhibitor MK-8353 in TNBC cells and prevents compensatory oncogenic pathway activation. Phosphoproteomics revealed that SCAMP3 affects phosphorylation of ERK feedback regulators Raf-1 (S43) and MEK2 (T394), ERK targets including nucleoporins and metabolic enzymes TPI1 and ACLY, and impairs mTORC1 signaling. SCAMP3 loss also disrupts autophagic flux, evidenced by elevated SQSTM1/p62 and LC3B-II with reduced Rab7A. TMT-based LC-MS/MS phosphoproteomics of WT vs SCAMP3 KO cells under EGF stimulation and ERK inhibitor treatment, immunoblotting International journal of molecular sciences Medium 41096842

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells. Cell 328 28388416
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2011 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 286 21903422
2010 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunology and cell biology 221 20458337
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2013 PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 204 24332808
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature 176 32433612
2017 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature communications 176 28685749
2004 Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Analytical chemistry 174 15144186
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2009 SCAMP3 is a component of the Salmonella-induced tubular network and reveals an interaction between bacterial effectors and post-Golgi trafficking. Cellular microbiology 60 19438519
2009 SCAMP3 negatively regulates epidermal growth factor receptor degradation and promotes receptor recycling. Molecular biology of the cell 57 19158374
1998 Tyrosine phosphorylation of selected secretory carrier membrane proteins, SCAMP1 and SCAMP3, and association with the EGF receptor. Molecular biology of the cell 34 9658162
2011 Regulation of the MVB pathway by SCAMP3. Traffic (Copenhagen, Denmark) 32 21951651
2019 MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed-forward loop during adipogenesis. Scientific reports 20 31554889
2021 SCAMP3 is a mutant EGFR phosphorylation target and a tumor suppressor in lung adenocarcinoma. Oncogene 12 33850265
2020 SCAMP3 is regulated by miR-128-3p and promotes the metastasis of hepatocellular carcinoma cells through EGFR-MAPK p38 signaling pathway. American journal of translational research 10 33437366
2022 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 9 35681787
2023 SCAMP3 promotes breast cancer progression through the c-MYC-β-Catenin-SQSTM1 growth and stemness axis. Cellular signalling 6 36627007
2020 Comprehensive Evaluation of Endocytosis-Associated Protein SCAMP3 in Hepatocellular Carcinoma. Pharmacogenomics and personalized medicine 6 33116758
2024 Optimized Proteomic Analysis of Insulin Granules From MIN6 Cells Identifies Scamp3, a Novel Regulator of Insulin Secretion and Content. Diabetes 5 39320956
2025 SCAMP3-Driven Regulation of ERK1/2 and Autophagy Phosphoproteomics Signatures in Triple-Negative Breast Cancer. International journal of molecular sciences 2 41096842
2025 SCAMP3 and EPS8 Cooperatively Regulate EGFR Signaling to Promote Enzalutamide Resistance and Metastatic Potential in Prostate Cancer. Cancer genomics & proteomics 0 41151858
2025 SCAMP3 is essential for proper formation and function of neutrophil granules. Journal of leukocyte biology 0 41187789
2021 SCAMP3 is regulated by miR-128-3p and promotes the metastasis of hepatocellular carcinoma cells through EGFR-MAPK p38 signaling pathway [Retraction]. American journal of translational research 0 35035772