Affinage

SPPL2A

Signal peptide peptidase-like 2A · UniProt Q8TCT8

Round 2 corrected
Length
520 aa
Mass
58.1 kDa
Annotated
2026-04-28
130 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPPL2A is a GxGD-type aspartyl intramembrane protease that resides on lysosomal/late endosomal membranes—directed there by a C-terminal YXXφ tyrosine sorting motif—where it sequentially cleaves the N-terminal fragments (NTFs) of type II transmembrane proteins following their ectodomain shedding (PMID:15385547, PMID:21896273). Its most critical physiological substrate is the CD74 (MHC class II invariant chain) NTF: SPPL2A cleaves CD74 between Y52 and F53 in the transmembrane segment, and loss of this activity causes toxic CD74 NTF accumulation that blocks B cell maturation at the T1 stage, impairs BCR/PI3K/Akt signalling, depletes cDC2 dendritic cells, and in humans causes Mendelian susceptibility to mycobacterial disease (PMID:23267015, PMID:26987812, PMID:30127434). Additional validated substrates include TNFα, FasL, Bri2, TMEM106B, LOX-1 NTFs, and VAMP1–4 SNAREs, through which SPPL2A regulates inflammatory cytokine signalling, apoptotic ligand turnover, and vesicular trafficking (PMID:16829952, PMID:17557115, PMID:17965014, PMID:36047592, PMID:30819724). SPPL2A-mediated clearance of LOX-1 NTFs suppresses ligand-independent MAP kinase activation and limits atherosclerotic plaque formation in vivo (PMID:30819724).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2004 High

    Establishing the membrane topology of SPPL2A resolved how a GxGD-type aspartyl protease could accommodate type II transmembrane substrates, because its active-site loops face the exoplasm—the opposite orientation to presenilins.

    Evidence Epitope-tagged constructs, glycosylation mapping, and protease protection assays in mammalian cells

    PMID:15385547

    Open questions at the time
    • No substrate identified at this stage
    • Subcellular compartment of endogenous protein not determined
    • No structural model at atomic resolution
  2. 2006 High

    Demonstrating that SPPL2A cleaves TNFα NTF in endosomes of primary dendritic cells provided the first substrate identification and showed that the released ICD has a signalling function (IL-12 induction), establishing SPPL2A as a functionally active intramembrane protease.

    Evidence Catalytic-dead mutant overexpression, subcellular fractionation, reporter assays for ICD release and IL-12 in primary human dendritic cells

    PMID:16829952

    Open questions at the time
    • Physiological importance of TNFα ICD signalling not confirmed in vivo
    • Other substrates not yet known
  3. 2007 High

    Identification of FasL and Bri2 as additional SPPL2A substrates demonstrated that the enzyme acts broadly on type II transmembrane protein NTFs generated by ADAM10 shedding, and that liberated ICDs can regulate nuclear transcription.

    Evidence Dominant-negative SPPL2A in T-cell lines (FasL); systematic family member comparison with catalytic-dead controls (Bri2)

    PMID:17557115 PMID:17965014

    Open questions at the time
    • In vivo consequences of FasL and Bri2 ICD signalling uncharacterised
    • Structural basis of substrate selectivity unknown
  4. 2011 High

    Mapping the YXXφ lysosomal targeting motif at Y498 in the SPPL2A C-terminal tail explained how SPPL2A is sorted to lysosomes/late endosomes and distinguished from its plasma-membrane homologue SPPL2B, establishing compartment-specific substrate access.

    Evidence Chimeric SPPL2A/SPPL2B constructs with point mutations, immunofluorescence of endogenous protein, live-cell imaging

    PMID:21896273

    Open questions at the time
    • Adaptor proteins mediating YXXφ-dependent sorting not identified
    • Quantitative contribution of lysosomal vs. endosomal pools unclear
  5. 2012 High

    Three independent mouse models converged on CD74 NTF as the physiologically dominant SPPL2A substrate: loss of SPPL2A caused toxic CD74 NTF accumulation that blocked B cell maturation at T1 and depleted CD8-negative DCs, with full rescue by concurrent CD74 deletion, establishing a non-redundant SPPL2A–CD74 axis in adaptive immunity.

    Evidence SPPL2A knockout, ENU mutant (chompB), and knock-in mouse models; flow cytometry, Western blot, genetic epistasis with CD74 KO, bone marrow transfer

    PMID:23267013 PMID:23267015 PMID:23267016

    Open questions at the time
    • Mechanism by which accumulated CD74 NTF disrupts endosomal trafficking incompletely defined
    • Whether other substrates contribute to immune phenotype unclear
  6. 2014 High

    Conservation of the SPPL2A–CD74 axis was validated in humans when patient-derived cells carrying a homozygous SPPL2A deletion accumulated CD74 NTF identically to mouse knockouts, and TMEM106B was identified as a neurodegenerative-disease-relevant lysosomal substrate.

    Evidence Patient lymphoblastoid cell lines with SPPL2A genomic deletion (CD74 NTF); co-expression and catalytic-dead mutant assays (TMEM106B)

    PMID:24872421 PMID:25035924

    Open questions at the time
    • Neurological phenotype in SPPL2A-deficient patients not assessed
    • In vivo relevance of TMEM106B cleavage to neurodegeneration untested
  7. 2015 High

    Defining how accumulated CD74 NTF physically associates with BCR and Syk to suppress tonic PI3K/Akt signalling and elevate FOXO1-dependent pro-apoptotic transcription provided a molecular explanation for the T1 B cell maturation block in SPPL2A deficiency.

    Evidence Co-immunoprecipitation of CD74 NTF with BCR components, phospho-flow cytometry for Akt/Syk, transcription factor analysis in SPPL2A−/− mouse B cells

    PMID:26157172

    Open questions at the time
    • Direct structural basis of CD74 NTF–BCR interaction unknown
    • Whether this mechanism operates in mature B cells or germinal centres untested
  8. 2016 High

    Mass spectrometry-based mapping of the primary SPPL2A cleavage site to Y52–F53 in the CD74 transmembrane helix, combined with systematic alanine scanning, revealed that helix flexibility (glycine residues) and the luminal juxtamembrane domain are key determinants of intramembrane proteolysis.

    Evidence IP-MS cleavage site identification, domain-exchange and alanine-scanning mutagenesis, cell-based cleavage assays

    PMID:26987812

    Open questions at the time
    • Atomic-resolution structure of SPPL2A–substrate complex not available
    • Rules for predicting novel substrates not generalised
  9. 2018 High

    Human inborn errors of SPPL2A were shown to selectively deplete cDC2s and impair IFN-γ production by mycobacterium-specific TH1* cells, establishing SPPL2A deficiency as a Mendelian cause of susceptibility to mycobacterial disease (BCG disease).

    Evidence Whole-exome sequencing, patient immunophenotyping, in vitro stimulation, Sppl2a−/− mouse BCG/M. tuberculosis infection model, genetic complementation

    PMID:30127434

    Open questions at the time
    • Full clinical spectrum of human SPPL2A deficiency beyond mycobacterial susceptibility not defined
    • Whether cDC2 loss is entirely CD74 NTF-dependent not formally demonstrated in patients
  10. 2019 High

    Expansion of the SPPL2A substrate repertoire to include VAMP1–4 SNAREs (degradative clearance) and LOX-1 NTFs (suppression of ligand-independent MAP kinase signalling and atherosclerosis) demonstrated that SPPL2A functions beyond immune regulation in vesicular trafficking homeostasis and cardiovascular pathology.

    Evidence Systematic SNARE cleavage screen and SPPL2A/B double-KO mouse tissues (VAMPs); co-IP, signalling assays, and atherosclerosis plaque quantification in double-KO mice (LOX-1)

    PMID:30819724 PMID:36047592

    Open questions at the time
    • Relative contribution of SPPL2A vs. SPPL2B to individual SNARE and LOX-1 processing in vivo unclear
    • Tissue-specific substrate hierarchy not mapped
  11. 2019 Medium

    A non-canonical ectodomain shedding activity of SPPL2A on TNFα, governed by transmembrane helix flexibility, raised the possibility that SPPL2A can operate in processing modes beyond classical intramembrane proteolysis.

    Evidence TM helix proline/leucine mutagenesis, CD and NMR structural analysis, molecular dynamics simulations

    PMID:33294784

    Open questions at the time
    • Physiological relevance of non-canonical shedding not demonstrated in vivo
    • Whether non-canonical activity applies to other substrates unknown
    • Single-lab observation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the atomic structure of SPPL2A, the complete substrate repertoire across tissues, generalizable rules predicting substrate recognition, the full clinical phenotype of human SPPL2A deficiency beyond mycobacterial susceptibility, and whether accumulated CD74 NTF is the sole driver of cDC2 depletion in patients.
  • No high-resolution structure of SPPL2A or SPPL2A–substrate complex
  • Tissue-specific substrate hierarchy and redundancy with SPPL2B not systematically defined
  • Therapeutic implications of modulating SPPL2A activity unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 3
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CD74FASLGITM2BOLR1TMEM106BTNFVAMP1VAMP2

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 SPPL2a is a polytopic membrane protein belonging to the GxGD-type aspartyl intramembrane protease family (SPP/SPPL family); its N-terminal extension is located in the extracellular space and is modified with N-glycans; the hydrophilic loops containing the catalytic residues face the exoplasm and the C-terminus faces the cytosol, placing it in opposite orientation to presenilins and predicting it cleaves type II-oriented substrate peptides. Comparative topology analysis using epitope-tagged constructs, glycosylation mapping, and protease protection assays The Journal of biological chemistry High 15385547
2006 SPPL2a is sorted to endosomes and functions as an active intramembrane protease that catalyses intramembrane cleavage of tumour necrosis factor alpha (TNFα), promoting release of the TNFα intracellular domain (ICD), which triggers IL-12 expression in activated human dendritic cells. Overexpression and catalytic-dead mutant constructs, subcellular fractionation/immunofluorescence for localization, reporter assays for ICD release and IL-12 induction in primary human dendritic cells Nature cell biology High 16829952
2007 SPPL2a mediates intramembrane cleavage of Fas ligand (FasL) in T-cells after prior ectodomain shedding by ADAM10; SPPL2a cleavage liberates the FasL intracellular domain (ICD), which translocates to the nucleus and inhibits gene transcription. Overexpression and dominant-negative SPPL2a in T-cell lines, immunoprecipitation, subcellular fractionation, luciferase transcription reporter assays; endogenous FasL processing validated Cell death and differentiation High 17557115
2007 SPPL2a and SPPL2b, but not SPP or SPPL3, mediate intramembrane proteolysis of Bri2 (Itm2b) N-terminal fragment generated after ADAM10 ectodomain shedding, producing an intracellular domain and a secreted low-molecular-weight C-terminal peptide. Expression of all SPP/SPPL family members and catalytic-dead variants, co-transfection with Bri2 constructs, immunoprecipitation, Western blot detection of cleavage products The Journal of biological chemistry High 17965014
2011 Endogenous SPPL2a localises to lysosomal/late endosomal membranes. Lysosomal targeting is mediated by a canonical tyrosine-based sorting motif (YXXø at position Y498) in its cytosolic C-terminal tail, which is both necessary and sufficient to direct SPPL2a to lysosomes/late endosomes and distinguishes it from its plasma-membrane-localised homologue SPPL2b. Immunofluorescence of endogenous SPPL2a, chimeric SPPL2a/SPPL2b constructs with point mutations in sorting motif, live-cell imaging FEBS letters High 21896273
2012 SPPL2a is the intramembrane protease responsible for cleavage of the invariant chain (CD74) N-terminal fragment (NTF) in lysosomes/late endosomes of B cells. Loss of SPPL2a in mice causes CD74 NTF accumulation that severely impairs endosomal membrane trafficking, reduces surface BAFF-R expression, causes MHCII accumulation, and leads to a block in B cell maturation at the T1 stage; all these defects are rescued by additional CD74 knockout. SPPL2a−/− mouse model, flow cytometry, Western blot, immunofluorescence, endocytic trafficking assays, genetic epistasis (CD74/SPPL2a double KO rescue) The Journal of experimental medicine High 23267015
2012 SPPL2a deficiency blocks proteolytic processing of CD74 MHC II invariant chain in B cells and CD8-negative dendritic cells, causing build-up of the p8 cathepsin-S product and interfering with earlier steps in CD74 endosomal retention. Loss of SPPL2a phenocopies BAFF deficiency; B cell survival is restored by BCL2 overexpression but not by BAFF. ENU mutagenesis screen (chompB mouse), positional cloning of Sppl2a mutation, proteomic identification of CD74 as substrate, flow cytometry, Western blot The Journal of experimental medicine High 23267013
2012 SPPL2a deficiency causes dramatic accumulation of the CD74 p8 NTF in B cells and CD8-negative dendritic cells, reduces surface IgM, IgD, and BAFF-R, and leads to a profound humoral immunodeficiency. The final step of the CD74-MHCII lysosomal processing pathway requires SPPL2a. Inactivating point mutation knock-in mouse, flow cytometry, Western blot, bone marrow transfer experiments The Journal of experimental medicine High 23267016
2013 SPPL2a is critical for tooth enamel formation; Sppl2a−/− mice exhibit defective enamel mineralisation and impaired maturation-stage ameloblast function with delayed and incomplete resorption of the proteinaceous enamel matrix, establishing a role for SPPL2a-mediated intramembrane proteolysis in ameloblast cellular homeostasis. Sppl2a−/− mouse model, micro-CT, histology, electron microscopy, immunohistochemistry for SPPL2a in enamel epithelium Journal of bone and mineral research Medium 23426979
2014 SPPL2a, and to a lesser extent SPPL2b, mediate intramembrane proteolysis of the frontotemporal lobar degeneration risk factor TMEM106B, generating and then rapidly degrading a small intracellular domain from the lysosome-localised N-terminal fragment of TMEM106B. TMEM106A, a paralogue, is not a specific SPPL2a substrate. Co-expression of SPPL2a/b with TMEM106B in cell lines, catalytic-dead mutant controls, lysosomal protease inhibitors, Western blot detection of NTF and ICD The Journal of biological chemistry Medium 24872421
2014 SPPL2a-mediated CD74 NTF processing is conserved in human B cells; lymphoblastoid cell lines from patients with a homozygous chromosomal microdeletion disrupting the SPPL2a locus lack SPPL2a protein and accumulate CD74 NTF comparably to Sppl2a−/− mouse B cells. Patient-derived lymphoblastoid cell lines with genomic SPPL2a deletion, Western blot for SPPL2a and CD74 NTF, genomic deletion mapping Biochemical and biophysical research communications High 25035924
2015 SPPL2a-mediated cleavage of the CD74 NTF is indispensable for tonic and BCR-induced PI3K/Akt signalling in transitional B cells. Accumulating CD74 NTF interacts with BCR and Syk, reducing surface IgM and dampening BCR signal transmission. SPPL2a deficiency also causes dysregulation of FOXO1, elevating transcription of pro-apoptotic genes. SPPL2a−/− mouse B cells, phospho-flow cytometry for Akt/Syk signalling, co-immunoprecipitation of CD74 NTF with BCR components, BCR trafficking assays, transcription factor analysis Journal of immunology High 26157172
2016 The primary SPPL2a cleavage site within CD74 is located between Y52 and F53 in the transmembrane segment. The intracellular domain of CD74 is dispensable for SPPL2a cleavage. Alanine substitution of helix-destabilising glycines in the CD74 transmembrane segment and distinct luminal membrane-proximal residues reduces SPPL2a cleavage efficiency, indicating that transmembrane helix flexibility and the luminal juxtamembrane domain facilitate intramembrane proteolysis. Domain-exchange constructs, alanine-scanning mutagenesis of CD74 TM and juxtamembrane region, IP-MS identification of primary cleavage site, cell-based cleavage assays The Biochemical journal High 26987812
2018 Inherited loss-of-function mutations in SPPL2A in humans cause selective depletion of IL-12/IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their progenitors due to toxic CD74 NTF accumulation, and impair IFN-γ production by mycobacterium-specific memory TH1* cells, resulting in susceptibility to mycobacterial disease (BCG disease). Whole-exome sequencing of patients, patient cell immunophenotyping (flow cytometry), in vitro stimulation assays, Sppl2a−/− mouse infection model (BCG and M. tuberculosis), genetic complementation Nature immunology High 30127434
2019 SPPL2a exhibits a non-canonical ectodomain shedding activity on TNFα that is distinct from classical intramembrane cleavage; proline insertions in the TNFα transmembrane helix strongly increase this SPPL2a non-canonical shedding, while leucine substitutions decrease it. Biophysical analysis identified a flexible region in the centre of the TNFα TM domain as critical for this processing mode. TM helix mutagenesis (proline/leucine insertions), biochemical shedding assays, circular dichroism and NMR structural analysis, molecular dynamics simulations iScience Medium 33294784
2019 SPPL2a and SPPL2b control cellular levels of VAMP1, VAMP2, VAMP3, and VAMP4 (tail-anchored SNARE proteins) by proteolytic degradation; loss of both proteases in double-KO mice causes cell-type- and tissue-dependent accumulation of VAMP1-4, establishing these SNAREs as in vivo substrates of SPPL2a/b. Cellular co-expression cleavage screen of 18 SNARE proteins, SPPL2a/b inhibitor treatment, Western blot of endogenous VAMP1-4 in primary cells and tissues from SPPL2a/b double-KO mice The FEBS journal High 36047592
2019 SPPL2a and SPPL2b control LOX-1 signalling by cleaving ADAM10-generated LOX-1 N-terminal fragments (NTFs) in lysosomes and at the plasma membrane, respectively. LOX-1 NTFs self-associate via their transmembrane domain and activate MAP kinases in a ligand-independent manner, upregulating pro-atherogenic targets (ICAM-1, CTGF). SPPL2a/b-deficient mice accumulate LOX-1 NTFs and develop larger atherosclerotic plaques. Co-expression and catalytic-dead mutant assays, co-IP for LOX-1 NTF self-association, MAP kinase signalling readouts, SPPL2a/b double-KO mouse atherosclerosis model (plaque quantification) The Journal of experimental medicine High 30819724

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature genetics 3440 24162737
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
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 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
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
2002 Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science (New York, N.Y.) 457 12077416
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2005 The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. The Journal of biological chemistry 192 15753088
2006 SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nature cell biology 165 16829952
2007 Integral and associated lysosomal membrane proteins. Traffic (Copenhagen, Denmark) 163 17897319
2010 Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 140 20562850
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2007 Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. The Journal of biological chemistry 135 17965014
2016 CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. Scientific reports 129 27510448
2013 Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 123 23969696
2008 The oncofetal protein IMP3: a novel biomarker for endometrial serous carcinoma. The American journal of surgical pathology 121 18223334
2006 A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b. Nature cell biology 119 16829951
2007 The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. Cell death and differentiation 112 17557115
2012 The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. The Journal of experimental medicine 106 23267015
2015 Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer. British journal of cancer 102 26158423
2006 IMP3 is a novel biomarker for adenocarcinoma in situ of the uterine cervix: an immunohistochemical study in comparison with p16(INK4a) expression. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 96 17192788
2012 Regulation of IMP3 by EGFR signaling and repression by ERβ: implications for triple-negative breast cancer. Oncogene 93 22266872
2018 Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nature immunology 92 30127434
2004 Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins. The Journal of biological chemistry 87 15385547
2019 Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3. Nature communications 81 31118463
2014 IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA decay in cancer and development. Cell reports 80 24703842
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2012 The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. The Journal of experimental medicine 75 23267013
2012 B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A. The Journal of experimental medicine 72 23267016
2007 Expression of a novel oncofetal mRNA-binding protein IMP3 in endometrial carcinomas: diagnostic significance and clinicopathologic correlations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 68 17885673
2013 IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression. The Journal of biological chemistry 64 23539627
2008 Combination of quantitative IMP3 and tumor stage: a new system to predict metastasis for patients with localized renal cell carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 64 18765551
2020 CircCDKN2B-AS1 interacts with IMP3 to stabilize hexokinase 2 mRNA and facilitate cervical squamous cell carcinoma aerobic glycolysis progression. Journal of experimental & clinical cancer research : CR 62 33308298
2015 IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 61 25982283
2010 Diagnostic usefulness of EMA, IMP3, and GLUT-1 for the immunocytochemical distinction of malignant cells from reactive mesothelial cells in effusion cytology using cytospin preparations. Diagnostic cytopathology 61 21574259
2002 Novel class of polytopic proteins with domains associated with putative protease activity. Biochemistry. Biokhimiia 61 12139484
2017 IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor. Cancer letters 59 29217458
2010 S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. Human pathology 57 20382408
2011 Oncofetal protein IMP3, a new diagnostic biomarker to distinguish malignant mesothelioma from reactive mesothelial proliferation. The American journal of surgical pathology 55 21566519
2009 An oncofetal protein IMP3: a new molecular marker for the detection of esophageal adenocarcinoma and high-grade dysplasia. The American journal of surgical pathology 55 19047899
2017 IMP3 overexpression occurs in various important cancer types and is linked to aggressive tumor features: A tissue microarray study on 8,877 human cancers and normal tissues. Oncology reports 54 29115542
2014 Comparative immunohistochemical analysis of IMP3, GLUT1, EMA, CD146, and desmin for distinguishing malignant mesothelioma from reactive mesothelial cells. American journal of clinical pathology 49 24343741
2012 Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression. Carcinogenesis 49 22859271
2013 Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization. Oncogene 47 23812426
2014 Oncofetal protein IMP3, a new cancer biomarker. Advances in anatomic pathology 45 24713990
2016 The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB. eLife 44 26982091
2005 Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries. DNA research : an international journal for rapid publication of reports on genes and genomes 43 16303743
2011 Diagnostic value of immunohistochemical IMP3 expression in core needle biopsies of pancreatic ductal adenocarcinoma. The American journal of surgical pathology 42 21566520
2011 Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late endosomes by a tyrosine motif in its C-terminal tail. FEBS letters 42 21896273
2014 Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). The Journal of biological chemistry 41 24872421
2009 IMP-3 is differentially expressed in normal and neoplastic lymphoid tissue. Human pathology 40 19698973
2015 Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression. PloS one 38 25919292
2022 A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins. Viruses 37 35337019
2012 Oncofetal protein IMP3: a useful diagnostic biomarker for leiomyosarcoma. Human pathology 36 22497850
2008 Use of IMP3 in identification of carcinoma in fine needle aspiration biopsies of pancreas. Acta cytologica 35 18499984
2019 Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. The Journal of experimental medicine 34 30819724
2018 IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer. Cell reports 34 29847788
2020 IMP3 accelerates the progression of prostate cancer through inhibiting PTEN expression in a SMURF1-dependent way. Journal of experimental & clinical cancer research : CR 31 32938489
2013 ER+ /PR+ /TFF3+ /IMP3- immunoprofile distinguishes endometrioid from serous and clear cell carcinomas of the endometrium: a study of 401 cases. Histopathology 31 23570281
2012 Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression in hepatocellular carcinoma. A clinicopathological analysis with emphasis on diagnostic value. Histopathology 31 22211286
2008 Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors. Human pathology 29 18547613
1990 In vivo measurements of ethanol concentration in rabbit brain by 1H magnetic resonance spectroscopy. Journal of neurochemistry 29 2313285
2015 Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells. Journal of immunology (Baltimore, Md. : 1950) 28 26157172
2009 Insulin-like growth factor mRNA binding protein 3 (IMP3) is differentially expressed in benign and malignant follicular patterned thyroid tumors. Endocrine pathology 28 19449140
2020 SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity. Journal of immunology (Baltimore, Md. : 1950) 27 32393512
2019 Sas10 controls ribosome biogenesis by stabilizing Mpp10 and delivering the Mpp10-Imp3-Imp4 complex to nucleolus. Nucleic acids research 27 30773582
2018 Structural basis of IMP3 RRM12 recognition of RNA. RNA (New York, N.Y.) 27 30135093
2010 Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores. BMC cancer 27 20591150
2017 IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65. Oncotarget 26 28465487
2014 IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma. Human pathology 26 24745619
1991 Identification, cloning and sequencing of the replication region of Lactococcus lactis ssp. lactis biovar. diacetylactis Bu2 citrate plasmid pSL2. FEMS microbiology letters 26 1884982
2023 TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing. Neuro-oncology 25 36215168
2015 IL-18-induced interaction between IMP3 and HuR contributes to COX-2 mRNA stabilization in acute myeloid leukemia. Journal of leukocyte biology 25 26342105
2009 IMP3 expression in human ovarian cancer is associated with improved survival. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 25 19620937
2009 Diagnostic utility of IMP3 in segregating metastatic melanoma from benign nevi in lymph nodes. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 25 19734845
2008 Expression of insulin-like growth factor-II mRNA binding protein 3 (IMP3) in osteosarcoma. Oncology research 24 19192721
2017 Immunohistochemical analysis of IMP3 and p53 expression in endoscopic ultrasound-guided fine needle aspiration and resected specimens of pancreatic diseases. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 23 29305088
2016 Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. The Biochemical journal 23 26987812
2012 Diagnostic utility of von Hippel-Lindau gene product, maspin, IMP3, and S100P in adenocarcinoma of the gallbladder. Human pathology 23 23079206
2014 IMP3 expression is associated with epithelial-mesenchymal transition in breast cancer. International journal of clinical and experimental pathology 22 25031719
2012 Use of IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies with atypical histology or suspicious for malignancy. Applied immunohistochemistry & molecular morphology : AIMM 22 22495381
2012 Up-regulation of Imp3 confers in vivo tumorigenicity on murine osteosarcoma cells. PloS one 22 23226335
2009 IMP-3 expression in melanocytic lesions. Journal of cutaneous pathology 22 19788446
2020 Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix. iScience 21 33294784
2013 The oncofetal protein IMP3: a novel biomarker and triage tool for premalignant atypical endometriotic lesions. Fertility and sterility 21 23473990
2011 The distribution of IGF2 and IMP3 in osteosarcoma and its relationship with angiogenesis. Journal of molecular histology 21 22042095
1987 Human rheumatoid factor crossidiotypes. II. Primary structure-dependent crossreactive idiotype, PSL2-CRI, present on Wa monoclonal rheumatoid factors is present on Bla and other IgM kappa monoclonal autoantibodies. The Journal of experimental medicine 21 3098895
2014 The oncofetal protein IMP3: a useful marker to predict poor clinical outcome in neuroendocrine tumors of the lung. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20 25144243
2013 Expression of insulin-like growth factor II mRNA-binding protein 3 (IMP3) in sacral chordoma. Journal of neuro-oncology 20 24135846
2010 Diagnostic utility of IMP3 expression in thyroid neoplasms: a quantitative RT-PCR study. Diagnostic molecular pathology : the American journal of surgical pathology, part B 20 20502182
2018 IMP3 promotes TNBC stem cell property through miRNA-34a regulation. European review for medical and pharmacological sciences 19 29771420
2017 IMP3 expression in biopsy specimens as a diagnostic biomarker for colorectal cancer. Human pathology 19 28412210
2014 Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. Biochemical and biophysical research communications 19 25035924
2014 IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status. Journal of cancer research and clinical oncology 19 25323937
2013 IMP-3 expression in keratoacanthomas and squamous cell carcinomas of the skin: an immunohistochemical study. European journal of histochemistry : EJH 19 23549465
2015 Chromosome 12p abnormalities and IMP3 expression in prepubertal pure testicular teratomas. Human pathology 18 26826410
2021 RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA. Journal of experimental & clinical cancer research : CR 17 34154626
2015 IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage. International journal of clinical and experimental pathology 17 26617820
2013 The intramembrane protease SPPL2A is critical for tooth enamel formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 16 23426979
2021 Diagnostic value of IMP3 and p53 immunohistochemical staining in EUS-guided fine-needle aspiration for solid pancreatic tumors. Scientific reports 15 34446759
2017 Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a marker that predicts presence of invasion in papillary biliary tumors. Human pathology 15 28089541
2020 Utility of pVHL, maspin, IMP3, S100P and Ki67 in the distinction of autoimmune pancreatitis from pancreatic ductal adenocarcinoma. Pathology, research and practice 14 32273198
2018 Diagnostic Value of S100p, IMP3, Maspin, and pVHL in the Differantial Diagnosis of Pancreatic Ductal Adenocarcinoma and Normal/chronic Pancreatitis in Fine Needle Aspiration Biopsy. Journal of cytology 14 30498299
2016 Diagnostic value of IMP3 and mesothelin in differentiating pancreatic ductal adenocarcinoma from chronic pancreatitis. Pathology, research and practice 14 26874572
2013 Imp3 unfolds stem structures in pre-rRNA and U3 snoRNA to form a duplex essential for small subunit processing. RNA (New York, N.Y.) 14 23980203
2017 IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells. Cancer biology & therapy 13 28485999
2015 EGF enhances low-invasive cancer cell invasion by promoting IMP-3 expression. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26386725
2014 Expression and clinical significance of IMP3 in microdissected premalignant and malignant pancreatic lesions. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 13 25183049
2013 The utility of PAX8 and IMP3 immunohistochemical stains in the differential diagnosis of benign, premalignant, and malignant endocervical glandular lesions. Gynecologic oncology 13 23618832
2011 The oncofetal protein IMP3: a novel molecular marker to predict aggressive meningioma. Archives of pathology & laboratory medicine 13 21809995
2023 Association of circulating tumor cells and IMP3 expression with metastasis of osteosarcoma. Frontiers in oncology 12 36937398
2022 The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins. The FEBS journal 12 36047592
2016 IMP-3 protects the mRNAs of cyclins D1 and D3 from GW182/AGO2-dependent translational repression. International journal of oncology 12 27840950
2013 Oncofetal protein IMP3: a new diagnostic biomarker for laryngeal carcinoma. Human pathology 12 23806529
2020 IGF2BP3 (IMP3) expression in angiosarcoma, epithelioid hemangioendothelioma, and benign vascular lesions. Diagnostic pathology 11 32293476
2016 Expression of insulin-like growth factor II mRNA binding protein 3 (IMP3) in enchondroma and chondrosarcoma. Pathology, research and practice 11 26948096
2023 Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. Histopathology 10 37140546
2017 IMP3 is upregulated in primary ovarian mucinous carcinoma and promotes tumor progression. American journal of translational research 10 28804555
2016 The role of S100P and IMP3 in the cytologic diagnosis of pancreatic adenocarcinoma. Journal of the Egyptian National Cancer Institute 10 27839709
2015 The oncofetal protein IMP3: a novel grading tool and predictor of poor clinical outcome in human gliomas. BioMed research international 10 25695077
2014 IMP3 as a cytoplasmic biomarker for early serous tubal carcinogenesis. Journal of experimental & clinical cancer research : CR 10 25038792
2010 Analysis of IMP3 expression in normal and neoplastic human pituitary tissues. Endocrine pathology 10 19898970