Affinage

SCYL3

Protein-associating with the carboxyl-terminal domain of ezrin · UniProt Q8IZE3

Round 2 corrected
Length
742 aa
Mass
82.9 kDa
Annotated
2026-04-28
46 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCYL3 (PACE-1) is an N-terminally myristoylated pseudokinase that localizes to the Golgi apparatus and lamellipodia, where it associates with ezrin and participates in intracellular membrane trafficking and cytoskeletal regulation (PMID:12651155, PMID:33753324). SCYL3 functions redundantly with SCYL1 to maintain motor neuron viability and TDP-43 nuclear proteostasis in vivo, as combined loss of both genes accelerates motor neuron degeneration and TDP-43 mislocalization in mice (PMID:29437892). In hepatocellular carcinoma, SCYL3 physically binds and stabilizes ROCK2, promoting actin stress fiber and focal adhesion formation, thereby driving tumor cell proliferation, migration, and metastasis (PMID:36440258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2003 Medium

    The initial identification of SCYL3 (PACE-1) as an ezrin-binding pseudokinase that localizes to the Golgi via N-terminal myristoylation established its dual association with endomembranes and the cortical cytoskeleton, raising the question of what trafficking or signaling functions it performs.

    Evidence Yeast two-hybrid screen, co-immunofluorescence, subcellular fractionation, kinase assays, and myristoylation-signal mutagenesis in mammalian cells

    PMID:12651155

    Open questions at the time
    • Ezrin interaction demonstrated only by yeast two-hybrid and co-localization without reciprocal co-immunoprecipitation from endogenous proteins
    • Functional consequence of Golgi localization and ezrin binding was not determined
    • Intrinsic pseudokinase versus scaffolding role not resolved
  2. 2018 High

    Genetic epistasis in mice revealed that SCYL3 shares a redundant, essential role with SCYL1 in motor neuron survival and TDP-43 nuclear proteostasis, establishing the first in vivo physiological function for SCYL3.

    Evidence Scyl1/Scyl3 double-knockout mouse model with histopathology, TDP-43 immunofluorescence, motor behavioral assays, and nerve morphometry

    PMID:29437892

    Open questions at the time
    • Molecular mechanism by which SCYL3 maintains TDP-43 localization is unknown
    • Whether the COPI-trafficking function underlies the motor neuron phenotype was not tested
    • Single-knockout of Scyl3 shows no overt phenotype, so cell-type-specific roles remain unclear
  3. 2021 Medium

    Characterization of the yeast ortholog Cex1 linked SCYL3-family proteins to COPI vesicle coat machinery, providing a mechanistic basis for their role in Golgi-to-ER retrograde trafficking and protein glycosylation.

    Evidence Co-immunoprecipitation with COPI subunits (Sec27, Sec28, Ret1), fluorescence microscopy showing Wbp1 mislocalization upon cex1Δ in S. cerevisiae

    PMID:33753324

    Open questions at the time
    • Direct interaction between mammalian SCYL3 and COPI subunits has not been demonstrated
    • Whether COPI-binding is conserved from yeast Cex1 to human SCYL3 requires validation
    • Structural basis of Cex1/COPI interaction is unresolved
  4. 2022 High

    Identification of ROCK2 as a direct binding partner stabilized by SCYL3 connected the pseudokinase to Rho-kinase-dependent cytoskeletal remodeling and provided a mechanistic explanation for its pro-metastatic activity in hepatocellular carcinoma.

    Evidence Co-immunoprecipitation, SCYL3 knockdown/overexpression in HCC cell lines, immunofluorescence for stress fibers and focal adhesions, and in vivo metastasis in a sleeping beauty transposon/Tp53 KO/c-Myc OE mouse model

    PMID:36440258

    Open questions at the time
    • Whether SCYL3-ROCK2 interaction occurs in non-cancer physiological contexts is unknown
    • How pseudokinase scaffolding stabilizes ROCK2 at a structural level is unresolved
    • Relationship between ROCK2 stabilization and Golgi/COPI trafficking functions is not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified model linking SCYL3's COPI-trafficking function, ezrin binding, ROCK2 stabilization, and TDP-43 proteostasis role has not been established; it remains unclear whether these represent distinct context-dependent activities or facets of a single scaffolding mechanism.
  • No structural or biochemical reconstitution of SCYL3 in any complex
  • Mammalian COPI interaction has not been directly tested
  • Cell-type-specific functions beyond motor neurons and hepatocytes are unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
EZRROCK2

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SCYL3 (identified as PACE-1) was discovered as a novel binding partner of the C-terminal domain of ezrin via yeast two-hybrid screen. PACE-1 localizes to the cytoplasmic face of the Golgi apparatus in a manner dependent on its N-terminal myristoylation consensus sequence, and co-localizes with ezrin in lamellipodia. Despite a putative N-terminal kinase domain, biochemical assays showed PACE-1 has associated rather than intrinsic kinase activity, classifying it as a pseudokinase. Yeast two-hybrid screen, co-localization by immunofluorescence, subcellular fractionation, biochemical kinase assay, mutational analysis of myristoylation signal Experimental cell research Medium 12651155
2017 A SCYL3-NTRK1 chromosomal rearrangement produces an oncogenic fusion protein in colorectal cancer. The SCYL3-NTRK1 fusion protein constitutively activates the TRKA kinase domain, driving cell proliferation and survival, and is sensitive to TRKA inhibitors including entrectinib. RNA sequencing/fusion gene identification, functional oncogenicity assays in cancer cell lines, inhibitor sensitivity testing Oncotarget Medium 28903424
2018 SCYL3 plays an overlapping role with SCYL1 in maintaining motor neuron viability in vivo. Although Scyl3 knockout mice have no overt phenotype alone, combined loss of Scyl1 and Scyl3 accelerates motor neuron degeneration, hindlimb paralysis, muscle wasting, and loss of large-caliber axons compared to Scyl1 single knockouts, and correlates with mislocalization of TDP-43 in spinal motor neurons, implicating SCYL1/SCYL3 in TDP-43 proteostasis. Scyl1/Scyl3 double-knockout mouse model, histopathology, immunofluorescence for TDP-43 localization, behavioral/motor function assays, nerve morphometry The Journal of neuroscience High 29437892
2021 The yeast SCYL3 ortholog Cex1 functions as a component of the COPI intracellular trafficking machinery, physically interacting with COPI coat subunits Sec27, Sec28, and Sec33 (Ret1/Cop1). Loss of Cex1 causes mislocalization of the N-glycosylation factor Wbp1, which interacts with Sec27 via a di-lysine motif, linking SCYL family proteins to COPI-mediated Golgi-to-ER trafficking and protein glycosylation. Co-immunoprecipitation, subcellular localization by fluorescence microscopy, genetic deletion (cex1Δ) with mislocalization phenotype readout Biology open Medium 33753324
2022 SCYL3 physically binds to ROCK2 (Rho kinase 2) via its C-terminal domain and regulates ROCK2 protein stability and transactivating activity. SCYL3-mediated ROCK2 stabilization increases formation of actin stress fibers and focal adhesions, promoting hepatocellular carcinoma cell proliferation, migration, and in vivo metastasis. Knockdown of SCYL3 attenuates these phenotypes, while endogenous overexpression in a Tp53 KO/c-Myc OE mouse model increases tumor development and metastasis. Co-immunoprecipitation, western blotting, immunofluorescence, SCYL3 knockdown/overexpression in HCC cells, in vivo tumor model (sleeping beauty transposon in Tp53 KO/c-Myc OE mice) JHEP reports High 36440258

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
1999 Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. The Journal of clinical endocrinology and metabolism 176 10443688
2010 Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proceedings of the National Academy of Sciences of the United States of America 151 20616008
2005 Proteolytic activation of alternative CCR1 ligands in inflammation. Journal of immunology (Baltimore, Md. : 1950) 144 15905581
2017 Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Science translational medicine 120 28381538
2015 Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15-CCR1 Chemokine Axis. Clinical cancer research : an official journal of the American Association for Cancer Research 117 26341919
2020 Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers. Acta pharmaceutica Sinica. B 116 33643817
1999 Cloning and characterization of arylamine N-acetyltransferase genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: increased expression results in isoniazid resistance. Journal of bacteriology 109 9973365
2012 Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer's disease. PloS one 108 22279551
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1996 A YAC contig of the human CC chemokine genes clustered on chromosome 17q11.2. Genomics 104 8661057
2004 Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein science : a publication of the Protein Society 92 15340161
1997 Molecular cloning of leukotactin-1: a novel human beta-chemokine, a chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist at CC chemokine receptors 1 and 3. Journal of immunology (Baltimore, Md. : 1950) 88 9548457
1998 HCC-2, a human chemokine: gene structure, expression pattern, and biological activity. Proceedings of the National Academy of Sciences of the United States of America 84 9600961
2016 Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis. Clinical cancer research : an official journal of the American Association for Cancer Research 81 27492974
1998 Characterization of CKbeta8 and CKbeta8-1: two alternatively spliced forms of human beta-chemokine, chemoattractants for neutrophils, monocytes, and lymphocytes, and potent agonists at CC chemokine receptor 1. Blood 74 9558365
2010 New genetic associations detected in a host response study to hepatitis B vaccine. Genes and immunity 69 20237496
2021 Eosinophil-derived chemokine (hCCL15/23, mCCL6) interacts with CCR1 to promote eosinophilic airway inflammation. Signal transduction and targeted therapy 66 33640900
2004 Angiogenic activity of human CC chemokine CCL15 in vitro and in vivo. FEBS letters 66 15251437
1997 The chemokine information source: identification and characterization of novel chemokines using the WorldWideWeb and expressed sequence tag databases. Journal of leukocyte biology 59 9129202
2011 Biochemical analysis of matrix metalloproteinase activation of chemokines CCL15 and CCL23 and increased glycosaminoglycan binding of CCL16. The Journal of biological chemistry 58 22147696
1999 Differential effects of leukotactin-1 and macrophage inflammatory protein-1 alpha on neutrophils mediated by CCR1. Journal of immunology (Baltimore, Md. : 1950) 58 10202040
2009 Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes. The Pediatric infectious disease journal 57 19258923
2009 A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal immunology 56 19812544
1997 Characterisation of macrophage inflammatory protein-5/human CC cytokine-2, a member of the macrophage-inflammatory-protein family of chemokines. European journal of biochemistry 54 9346309
2013 Modulation of cytokine release and gene expression by the immunosuppressive domain of gp41 of HIV-1. PloS one 52 23383108
2010 Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls. Pediatric pulmonology 51 20503287
2001 Hemofiltrate CC chemokines with unique biochemical properties: HCC-1/CCL14a and HCC-2/CCL15. Journal of leukocyte biology 38 11527984
2004 Human LZIP binds to CCR1 and differentially affects the chemotactic activities of CCR1-dependent chemokines. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 15001559
2017 Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient. Oncotarget 31 28903424
2021 Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2. Biomedicines 27 34356872
2019 Low-Carbohydrate Training Increases Protein Requirements of Endurance Athletes. Medicine and science in sports and exercise 25 31083047
2018 Overlapping Role of SCYL1 and SCYL3 in Maintaining Motor Neuron Viability. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 29437892
2016 SCYL pseudokinases in neuronal function and survival. Neural regeneration research 22 26981075
2003 PACE-1, a novel protein that interacts with the C-terminal domain of ezrin. Experimental cell research 19 12651155
2022 SCYL3, as a novel binding partner and regulator of ROCK2, promotes hepatocellular carcinoma progression. JHEP reports : innovation in hepatology 11 36440258
1997 Endothelin-1 limits increases in blood flow to native and collateral-dependent myocardium. The American journal of physiology 8 9249531
2022 Dissecting protein function in vivo: Engineering allelic series in mice using CRISPR-Cas9 technology. Methods in enzymology 4 35525561
2013 Non-Parkinson movement disorders: Five new things. Neurology. Clinical practice 3 23634381
2019 A bacterial phyla dataset for protein function prediction. Data in brief 2 31921945
2010 Analysis on the susceptibility genes in two chinese pedigrees with familial Parkinson's disease. Neurology research international 1 21188226
2024 Bayesian colocalization of GWAS and eQTL signals reveals cell type-specific genes and regulatory variants for susceptibility to subtypes of ischemic stroke. Computational biology and chemistry 0 38744227
2021 Cex1 is a component of the COPI intracellular trafficking machinery. Biology open 0 33753324