Affinage

MADD

MAP kinase-activating death domain protein · UniProt Q8WXG6

Length
1647 aa
Mass
183.3 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MADD is a multifunctional DENN-domain guanine-nucleotide exchange factor (GEF) that activates Rab3 and Rab27 subfamily GTPases to drive regulated, Ca2+-dependent exocytosis across diverse secretory systems (PMID:20937701, PMID:16473592). As a Rab3 GEF it loads lipid-modified Rab3A/B/C/D with GTP and controls Ca2+-dependent vesicular release, and it preferentially binds GTP-Rab3 as an effector while serving as cargo for KIF1Bbeta/KIF1A motors that transport MADD and Rab3 down axons in a nucleotide-state-dependent manner (PMID:18849981, PMID:16473592). Family-wide and tissue-specific studies established MADD as the GEF for Rab27A/B, an activity required for amylase release from parotid acinar cells, glucose-induced insulin secretion from pancreatic beta-cells, histamine-evoked von Willebrand factor release from endothelial Weibel-Palade bodies, and degranulation/cytotoxicity of NK and CD8+ T cells; in lymphocytes MADD controls the Rab27a activation step rather than granule trafficking to the synapse (PMID:20937701, PMID:23702376, PMID:24379354, PMID:34551092, PMID:38506245). The endocytic GTPase Rab11A physically couples recycling endosomes to secretory vesicles by binding and activating the MADD/Rab27B pathway (PMID:37604243). Independently of its GEF function, MADD binds the death domain of TNFR1 through its own C-terminal death domain and couples TNFR1 specifically to ERK/MAPK activation by recruiting Grb2 and Sos1/2, while competing with TRADD for TNFR1 (PMID:9115275, PMID:15007167, PMID:19289468). MADD also acts as a pro-survival factor by directly binding TRAIL death receptors DR4/DR5 to block FADD and caspase-8 recruitment; this protection requires Akt-mediated phosphorylation at three conserved sites, and dephosphorylated MADD relocates to the cytoplasm, binds 14-3-3 to displace Bax, and triggers the mitochondrial apoptotic pathway (PMID:17314102, PMID:20484047, PMID:24038283). Alternative splicing of the IG20/MADD locus generates isoforms with opposing activities, with the MADD variant necessary and sufficient for cancer cell survival and the IG20 variant promoting death-receptor apoptosis (PMID:11577081, PMID:15208670, PMID:16682944). Biallelic loss-of-function MADD variants in patients cause cellular defects in TNF-alpha/ERK signaling, vesicular trafficking, and Weibel-Palade body secretion competence (PMID:40668965, PMID:32761064).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established MADD's first molecular role by showing it physically links TNFR1 to MAP kinase signaling, defining it as a death-domain adaptor rather than merely a death-inducing factor.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and overexpression assays in human cells

    PMID:9115275

    Open questions at the time
    • Did not establish which endogenous isoform mediates the interaction
    • Direct vs indirect coupling to ERK machinery not defined
  2. 2001 High

    Showed that splice variants of the same gene exert opposing effects on TNF-alpha apoptosis, reframing MADD/IG20 as a locus whose isoform balance tunes cell fate.

    Evidence Stable transfection of HeLa cells, caspase assays, Co-IP, flow cytometry

    PMID:11577081

    Open questions at the time
    • Structural basis for opposing isoform activities unresolved
    • Endogenous isoform ratios in normal vs tumor tissue not measured
  3. 2004 Medium

    Defined MADD as a competitor of TRADD at TNFR1 and showed its loss kills neurons, while a separate study showed the pro-apoptotic IG20 variant promotes DR4/DR5 DISC assembly, beginning to dissect isoform-specific death-receptor outputs.

    Evidence Co-IP competition assays, antisense knockdown in primary neurons, colocalization and DN-FADD/caspase-inhibitor experiments

    PMID:15007167 PMID:15208670

    Open questions at the time
    • Single-lab Co-IP competition without quantitative affinity
    • Did not separate direct receptor binding from downstream DISC effects
  4. 2006 High

    Demonstrated by isoform-selective knockdown and rescue that the MADD variant alone is necessary and sufficient for cancer cell survival, elevating it from a signaling adaptor to a survival dependency.

    Evidence Exon-specific shRNA knockdown with rescue re-expression, flow cytometry across multiple cancer lines

    PMID:16682944

    Open questions at the time
    • Survival mechanism downstream of MADD not yet defined here
    • Generalizability beyond tested cancer lines unaddressed
  5. 2007 High

    Resolved the survival mechanism by showing MADD directly binds DR4/DR5 (but not FADD or caspase-8) and acts as a negative regulator of caspase-8 activation at the receptor.

    Evidence Immunoprecipitation (negative for caspase-8/FADD), shRNA knockdown, caspase-8 assays, CrmA/DN-FADD rescue

    PMID:17314102

    Open questions at the time
    • Stoichiometry of MADD-DR4/DR5 occupancy unknown
    • Structural interface not defined
  6. 2008 High

    Connected MADD to motor-driven trafficking by showing it binds the stalk of KIF1Bbeta/KIF1A, acts as a GTP-Rab3 effector, and is required for axonal transport of Rab3.

    Evidence Reciprocal Co-IP, direct binding assays, sequential genetic knockouts, live axonal transport imaging

    PMID:18849981

    Open questions at the time
    • Relationship between GEF activity and motor binding not integrated
    • Regulation of cargo handoff unresolved
  7. 2009 High

    Pinpointed the signaling specificity of MADD by showing endogenous MADD is required for TNF-alpha-induced ERK (not JNK, p38, or NF-kappaB) via Grb2/Sos1/2 recruitment to TNFR1.

    Evidence Isoform-selective shRNA with rescue, multiplexed kinase and reporter assays, TNFR1 complex Co-IP

    PMID:19289468

    Open questions at the time
    • Direct vs scaffolded recruitment of Grb2/Sos not structurally defined
    • Reconciliation with earlier JNK-activation observation not addressed
  8. 2010 High

    Defined the biochemical core of MADD as a DENN-domain GEF for Rab3 and Rab27A/B and showed Akt phosphorylation at three sites gates its death-receptor binding, unifying the secretory and survival functions under a single regulated scaffold.

    Evidence Family-wide GEF/Rab-GTP loading assays; phosphosite mapping with DN-Akt and PI3K inhibition, Co-IP

    PMID:20484047 PMID:20937701

    Open questions at the time
    • Whether GEF and death-receptor functions occur on the same molecules simultaneously is unclear
    • Kinetics of TRAIL-induced dephosphorylation not quantified
  9. 2013 High

    Extended MADD GEF function to physiological secretion by showing its Rab27 activity is required for amylase release and that beta-cell knockout causes a glucose-induced insulin secretion defect.

    Evidence Antibody microinjection in permeabilized acinar cells with Rab27-GTP pull-down; conditional beta-cell knockout mouse with secretion and processing assays

    PMID:23702376 PMID:24379354

    Open questions at the time
    • Acinar antibody-block study is single-lab and indirect
    • Upstream Ca2+/signaling control of MADD GEF activity in beta-cells undefined
  10. 2014 Medium

    Closed the survival-to-death switch by showing PTEN-driven MADD dephosphorylation relocates MADD to the cytoplasm, where it binds 14-3-3 to release Bax and trigger mitochondrial apoptosis.

    Evidence siRNA knockdown, subcellular fractionation, Co-IP of MADD-14-3-3-Bax, cytochrome c release assays

    PMID:24038283

    Open questions at the time
    • Single-lab fractionation evidence for translocation
    • Direct competition of MADD vs Bax for 14-3-3 not quantified
  11. 2021 High

    Established MADD as the GEF activating Rab27A/Rab3B/Rab3D for Weibel-Palade body targeting and VWF release, and showed catalytic GEF activity and cytosolic localization—not just Rab binding—are required.

    Evidence siRNA, GTP-pull-down across multiple Rabs, DENN-domain mutants, TOMM70 mistargeting, VWF secretion assay

    PMID:34551092

    Open questions at the time
    • How MADD is recruited to specific vesicle classes not resolved
    • Coordination among the multiple Rab substrates unclear
  12. 2023 Medium

    Linked endocytic recycling to secretion by showing Rab11A physically binds and activates the MADD/Rab27B pathway downstream of CaSR/PI3K signaling.

    Evidence Co-IP, Rab activity assays, PI3K inhibitors, siRNA, cytokine secretion assays

    PMID:37604243

    Open questions at the time
    • Direct vs indirect Rab11A-MADD interaction not distinguished
    • Single-lab; physiological generality untested
  13. 2024 High

    Cemented MADD's secretory role and its disease relevance through patient cells: biallelic loss abolishes MADD protein and Rab27A/Rab3D activation, impairing WPB exocytosis and VWF secretion, while MADD knockout blocks the Rab27a-activation step required for cytotoxic lymphocyte degranulation; a splice variant retaining GEF activity still causes endocrine defects, implicating protein-protein interactions beyond catalysis.

    Evidence Patient-derived ECFC proteomics and live imaging; CRISPR knockout in NK/CD8+ cells with GTP pull-down and cytotoxicity; stem cell-derived islet/gonadotrope dex30 models with GEF assays

    PMID:38506245 PMID:38775154 PMID:40668965

    Open questions at the time
    • Non-catalytic interaction partners driving dex30 phenotype not identified
    • Tissue-specific determinants of clinical variability unresolved
  14. 2024 Medium

    Identified an upstream expression-control mechanism whereby lactylated nucleolin promotes productive MADD translation by bypassing a splicing-induced premature stop codon, driving downstream ERK signaling in a tumor context.

    Evidence Mass spectrometry, RNA splicing analysis, interaction assays, xenograft model, siRNA

    PMID:38679071

    Open questions at the time
    • Single-lab; metabolic-to-MADD regulation not validated in other tissues
    • Direct effect on MADD isoform balance in vivo unquantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how MADD's GEF/secretory functions and its death-receptor/MAPK scaffold functions are coordinated within a single cell, and what governs the choice between them.
  • No structural model integrating DENN GEF activity with death-domain signaling
  • Spatiotemporal partitioning of MADD pools across membranes not mapped
  • In vivo phosphorylation-state regulation of the survival/death switch undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 1
Partners
14-3-3DR4DR5GRB2KIF1AKIF1BRAB11ATNFR1
Complex memberships
TNFR1 signaling complexTRAIL DISC (DR4/DR5)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MADD associates with the death domain of TNFR1 through its own C-terminal death domain, co-immunoprecipitates with TNFR1, and overexpression of MADD activates ERK MAP kinase; expression of the MADD death domain stimulates both ERK and JNK MAP kinases and induces phosphorylation of cytosolic phospholipase A2. Yeast two-hybrid, co-immunoprecipitation, overexpression assays The Journal of biological chemistry High 9115275
2001 IG20 and DENN-SV (splice variants of the same gene as MADD) exert opposing effects on TNF-alpha-induced apoptosis: IG20 enhances caspase-8 and caspase-3 activation and renders cells more susceptible to apoptosis, while DENN-SV reduces caspase activation and confers resistance. All variants interact with TNFR1 and activate ERK and NF-kappaB. Stable transfection of HeLa cells, caspase activity assays, co-immunoprecipitation, flow cytometry The Journal of biological chemistry High 11577081
2004 DENN/MADD and TRADD competitively bind to TNFR1; overexpressed DENN/MADD abrogates TNFR1 binding to TRADD. Antisense knockdown of DENN/MADD in rat hippocampal neurons reduces endogenous DENN/MADD and promotes neuronal cell death. Overexpression in N2A cells, co-immunoprecipitation, antisense oligonucleotide knockdown in primary cultures, immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America Medium 15007167
2004 IG20 (proapoptotic splice variant of MADD/IG20 gene) interacts with TRAIL death receptors DR4 and DR5 and increases recruitment of FADD and caspase-8 into the TRAIL DISC, thereby enhancing TRAIL-induced apoptosis. Colocalization imaging, co-immunoprecipitation, dominant-negative FADD expression, caspase inhibitor experiments Oncogene Medium 15208670
2006 Selective knockdown of the MADD splice variant (using exon-specific shRNAs) results in spontaneous apoptosis of cancer cells; re-expression of MADD alone (without other IG20 isoforms) is sufficient to rescue cells from apoptosis, demonstrating MADD is necessary and sufficient for cancer cell survival. Exon-specific shRNA knockdown, lentiviral delivery, rescue re-expression, flow cytometry apoptosis assays Oncogene High 16682944
2007 MADD directly interacts with death receptors (DR4/DR5) but not with caspase-8 or FADD, and functions as a negative regulator of caspase-8 activation at death receptors. Knockdown of MADD leads to caspase-8 activation at death receptors and sensitizes cancer cells to TRAIL-induced apoptosis. Immunoprecipitation, shRNA knockdown, caspase-8 activation assays, CrmA and DN-FADD rescue experiments The Journal of biological chemistry High 17314102
2008 DENN/MADD (Rab3-GEP) directly interacts with the stalk domain of KIF1Bbeta and KIF1A motors and preferentially binds GTP-Rab3 (acting as a Rab3 effector). Sequential genetic perturbations showed KIF1Bbeta/KIF1A are required for transport of DENN/MADD and Rab3, and DENN/MADD is essential for axonal transport of Rab3. GTP-Rab3 is more efficiently transported than GDP-Rab3. Co-immunoprecipitation, direct binding assays, genetic knockouts (sequential), live imaging of axonal transport Nature cell biology High 18849981
2009 Endogenous MADD is specifically required for TNF-alpha-induced activation of MAPK/ERK (but not JNK, p38, or NF-kappaB, and not EGF-induced MAPK activation). MADD loss reduces Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreases Ras and MEKK1/2 activation. Re-expression of shRNA-resistant MADD rescues cells from TNF-alpha-induced apoptosis. Exon-specific shRNA knockdown, kinase activation assays (ERK, JNK, p38), NF-kappaB reporter assays, TNFR1 complex immunoprecipitation, rescue re-expression The Journal of biological chemistry High 19289468
2010 MADD is phosphorylated at three conserved sites by Akt; only phosphorylated MADD directly interacts with TRAIL receptor DR4, preventing FADD recruitment. TRAIL induces reduction in MADD phosphorylation in susceptible cells, causing MADD dissociation from DR4 and allowing DISC formation. In TRAIL-resistant cells, MADD phosphorylation is maintained. Phosphorylation assays, co-immunoprecipitation, dominant-negative Akt expression, PI3K inhibitor (LY294002), Western blotting The Journal of biological chemistry High 20484047
2010 MADD activates Rab27A and Rab27B as a DENN-domain GDP/GTP exchange factor, as demonstrated in a systematic characterization of 17 human DENN domain proteins; MADD-specific GEF activity toward Rab27A/27B was established in this family-wide study. GEF activity assays, Rab-GTP loading assays, localization studies across DENN family members The Journal of cell biology High 20937701
2013 MADD/DENN/Rab3GEP functions as a GEF for Rab27 in rat parotid acinar cells: an antibody against the C-terminal 150 amino acids of MADD inhibited isoproterenol-induced amylase release and reduced GTP-Rab27 levels in permeabilized cells, indicating MADD's GEF activity for Rab27 is required for regulated exocytosis. Antibody microinjection into streptolysin O-permeabilized acinar cells, Rab27-GTP pull-down assay, amylase release assay, RT-PCR Archives of biochemistry and biophysics Medium 23702376
2013 Conditional knockout of IG20/MADD in pancreatic beta-cells results in hyperglycemia and glucose intolerance due to a severe defect in glucose-induced insulin release (not insulin processing), with increased insulin accumulation in beta-cells. Conditional knockout mouse model (KMA1ko), glucose tolerance tests, insulin secretion assays, insulin processing analysis, immunostaining Diabetes High 24379354
2014 PTEN upregulation reduces MADD phosphorylation by Akt; non-phosphorylated MADD translocates from the plasma membrane to the cytoplasm where it binds 14-3-3, displacing Bax which then translocates to mitochondria causing cytochrome c release and apoptosis. PTEN siRNA knockdown prevents TRAIL-induced reduction in phospho-MADD. siRNA knockdown, Western blotting, subcellular fractionation, co-immunoprecipitation, cytochrome c release assay Journal of cellular biochemistry Medium 24038283
2021 MADD acts as the GEF for Rab27A, Rab3B, and Rab3D in primary human endothelial cells, driving their activation and recruitment to Weibel-Palade bodies (WPBs). MADD silencing reduces GTP-Rab27A, Rab3B, and Rab3D levels, decreases Rab localization to WPBs, and impairs histamine-evoked VWF release. The DENN domain of MADD is required for Rab activation but not binding. Cytosolic localization of MADD is essential for WPB targeting of Rabs. siRNA knockdown, Rab activity (GTP-pull-down) assays, DENN-domain mutant constructs, TOMM70 mistargeting experiment, immunofluorescence, VWF secretion assay Blood advances High 34551092
2024 Patient-derived endothelial cells (ECFCs) with biallelic MADD variants lack MADD protein, show reduced Rab27A and Rab3D activity and their failure to localize to WPBs, and have significantly reduced histamine-induced VWF and VWF propeptide secretion due to delayed and reduced WPB degranulation, establishing MADD as required for WPB secretion competence. Patient-derived ECFC isolation, proteomics, Rab activity assays, live-cell imaging of WPB exocytosis, VWF secretion assays Blood High 40668965
2024 MADD knockout significantly decreases GTP-bound Rab27a in NK cells and CD8+ T cells; MADD-deficient cytotoxic lymphocytes show severely reduced degranulation and cytolytic ability similar to Rab27a-deficient cells. MADD colocalizes with Rab27a on lytic granules and is enriched at the cytolytic synapse, but loss of MADD does not affect Rab27a association with lytic granules or their recruitment to the synapse. CRISPR knockout, Rab27a-GTP pull-down assay, degranulation assays (CD107a), cytotoxicity assays, confocal imaging Journal of cell science High 38506245
2005 Recombinant Rab3 GEP (DENN/MADD) is active as a GEF on lipid-modified Rab3A, Rab3B, Rab3C, and Rab3D but is inactive on lipid-unmodified Rab3A or Rab3A complexed with Rab GDI. Overexpression of Rab3 GEP inhibits Ca2+-dependent exocytosis from PC12 cells. Biochemical purification of recombinant protein from Sf9 cells, in vitro GEF activity assay, human growth hormone co-expression exocytosis assay in PC12 cells Methods in enzymology High 16473592
2020 Patient-derived fibroblasts with biallelic MADD variants show reduced phosphorylation of ERK1/2 upon TNF-alpha treatment, enhanced activation of caspase-3 and -7, increased apoptosis, and a defect in endocytosis of epidermal growth factor, demonstrating that MADD deficiency causes multiple cellular defects in TNF-alpha signaling and vesicular trafficking. Patient-derived fibroblast functional assays, Western blotting for pERK1/2, caspase activation assays, EGF endocytosis assay, mRNA/protein quantification Brain : a journal of neurology High 32761064
2024 Nucleolin lactylated at K477 by P300 (in response to glycolysis) binds the primary transcript of MADD and promotes efficient MADD translation by circumventing alternative splicing that generates a premature termination codon; lactylated NCL upregulates MADD expression and activates downstream ERK signaling. Mass spectrometry, macromolecule interaction assays, RNA splicing analysis, xenograft tumor model, Western blotting, siRNA knockdown Journal of hepatology Medium 38679071
2023 CaSR activation drives Rab11A-dependent coupling of recycling endosomes to secretory vesicles via endosomal PI3K-mediated activation of a MADD/Rab27B pathway. Rab11A physically interacts with and activates MADD (GEF for Rab3 and Rab27A/B), linking endocytic and secretory pathways. Co-immunoprecipitation, Rab activity assays, PI3K inhibitors, siRNA knockdown, cytokine secretion assays Cellular signalling Medium 37604243
2024 A splice site variant in MADD causing skipping of exon 30 (in-frame deletion of 36 amino acids) reduces insulin content and increases proinsulin-to-insulin ratio in stem cell-derived pancreatic islets, and decreases luteinizing hormone expression in gonadotrope cells; the GDP/GTP exchange activity of dex30 MADD remains intact, suggesting the endocrine phenotype arises through altered protein-protein interactions rather than loss of GEF catalytic function. Human embryonic stem cell-derived pancreatic islets, CRISPR-engineered dex30 cell lines, insulin/proinsulin ELISA, LH expression assay, protein-protein interaction proteomics, GEF activity assay JCI insight Medium 38775154
1996 The DENN protein (identical to MADD) localizes predominantly to the cell membrane with some cytoplasmic staining as determined by immunofluorescent labeling of human cells with polyclonal antibodies, and was identified as a 140–145 kDa protein on Western blots. Immunofluorescence, Western blotting with polyclonal antisera DNA sequence : the journal of DNA sequencing and mapping Low 8988362

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. The Journal of cell biology 280 20937701
2013 The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics (Oxford, England) 269 23329412
2012 Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Frontiers in genetics 210 23248642
2011 DENN domain proteins: regulators of Rab GTPases. The Journal of biological chemistry 205 21330364
2008 KIF1Bbeta- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD. Nature cell biology 180 18849981
2010 Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. Journal of inherited metabolic disease 174 21110228
2010 The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes. Molecular cell 164 20159556
1997 MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. The Journal of biological chemistry 149 9115275
2004 Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 114 15007167
2011 Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate. Proceedings of the National Academy of Sciences of the United States of America 98 22065758
2024 Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD. Journal of hepatology 92 38679071
2001 uDENN, DENN, and dDENN: indissociable domains in Rab and MAP kinases signaling pathways. Biochemical and biophysical research communications 82 11563850
2011 Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A. Journal of molecular medicine (Berlin, Germany) 81 21347544
2015 MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin. Neuron 77 26028574
2010 The tripartite motif protein MADD-2 functions with the receptor UNC-40 (DCC) in Netrin-mediated axon attraction and branching. Developmental cell 61 20627077
2001 Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alpha-induced apoptosis and activation of caspase-8 and -3. The Journal of biological chemistry 60 11577081
2006 Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 17182770
2009 Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD). PloS one 51 20020044
2016 Downregulation of miR-522 suppresses proliferation and metastasis of non-small cell lung cancer cells by directly targeting DENN/MADD domain containing 2D. Scientific reports 50 26783084
2009 MADD, a splice variant of IG20, is indispensable for MAPK activation and protection against apoptosis upon tumor necrosis factor-alpha treatment. The Journal of biological chemistry 44 19289468
2020 Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies. The international journal of biochemistry & cell biology 42 33279678
2004 IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs. Oncogene 41 14716293
2011 MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans. Developmental cell 39 22014523
2010 Akt-phosphorylated mitogen-activated kinase-activating death domain protein (MADD) inhibits TRAIL-induced apoptosis by blocking Fas-associated death domain (FADD) association with death receptor 4. The Journal of biological chemistry 37 20484047
2016 Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease. Revue neurologique 36 27038534
2004 IG20 (MADD splice variant-5), a proapoptotic protein, interacts with DR4/DR5 and enhances TRAIL-induced apoptosis by increasing recruitment of FADD and caspase-8 to the DISC. Oncogene 35 15208670
2004 Dual role of DENN/MADD (Rab3GEP) in neurotransmission and neuroprotection. Trends in molecular medicine 34 15464446
1996 DENN, a novel human gene differentially expressed in normal and neoplastic cells. DNA sequence : the journal of DNA sequencing and mapping 34 8988362
2020 Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder. Brain : a journal of neurology 32 32761064
2018 A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy. JIMD reports 32 30311138
2010 MADD-2, a homolog of the Opitz syndrome protein MID1, regulates guidance to the midline through UNC-40 in Caenorhabditis elegans. Developmental cell 32 20627078
2006 MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival. Oncogene 32 16682944
1999 Implication of TNF receptor-I-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation in growth of AIDS-associated Kaposi's sarcoma cells: a possible role of a novel death domain protein MADD in TNF-alpha-induced ERK1/2 activation in Kaposi's sarcoma cells. Journal of immunology (Baltimore, Md. : 1950) 32 10092829
2021 GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies. Blood advances 31 34551092
2012 Equine multiple acyl-CoA dehydrogenase deficiency (MADD) associated with seasonal pasture myopathy in the midwestern United States. Journal of veterinary internal medicine 31 22708588
2013 MADD knock-down enhances doxorubicin and TRAIL induced apoptosis in breast cancer cells. PloS one 30 23457619
2023 Acute myeloid leukemia-derived exosomes deliver miR-24-3p to hinder the T-cell immune response through DENN/MADD targeting in the NF-κB signaling pathways. Cell communication and signaling : CCS 29 37735672
2007 MADD/DENN splice variant of the IG20 gene is a negative regulator of caspase-8 activation. Knockdown enhances TRAIL-induced apoptosis of cancer cells. The Journal of biological chemistry 29 17314102
2015 Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein. Open biology 28 26631379
2013 MADD/DENN/Rab3GEP functions as a guanine nucleotide exchange factor for Rab27 during granule exocytosis of rat parotid acinar cells. Archives of biochemistry and biophysics 27 23702376
2013 Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation. Molecular genetics and metabolism 26 23628458
2011 Knockdown of MADD and c-FLIP overcomes resistance to TRAIL-induced apoptosis in ovarian cancer cells. American journal of obstetrics and gynecology 26 21855847
2008 Regulation of apoptosis and caspase-8 expression in neuroblastoma cells by isoforms of the IG20 gene. Cancer research 26 18794122
2013 IG20/MADD plays a critical role in glucose-induced insulin secretion. Diabetes 25 24379354
2004 Antisense abrogation of DENN expression induces apoptosis of leukemia cells in vitro, causes tumor regression in vivo and alters the transcription of genes involved in apoptosis and the cell cycle. International journal of cancer 25 14735464
2019 Late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD): case reports and epidemiology of ETFDH gene mutations. BMC neurology 24 31852447
2013 LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans. eLife 24 23539368
2007 Equine biochemical multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of rhabdomyolysis. Molecular genetics and metabolism 24 17540595
2019 DENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes. Biochimica et biophysica acta. Molecular cell research 23 30771381
2015 Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways. Oncotarget 22 26517243
2015 A case of late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (MADD) with a novel mutation in ETFDH gene. Journal of the neurological sciences 21 25913573
1998 The human DENN gene: genomic organization, alternative splicing, and localization to chromosome 11p11.21-p11.22. Genome 21 9796103
2019 Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer. Cell death & disease 20 30760700
2002 Induction of marked apoptosis in mammalian cancer cell lines by antisense DNA treatment to abolish expression of DENN (differentially expressed in normal and neoplastic cells). Molecular carcinogenesis 20 12410563
2008 Role of IG20 splice variants in TRAIL resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 19 18223207
2022 A cell-based GEF assay reveals new substrates for DENN domains and a role for DENND2B in primary ciliogenesis. Science advances 17 35196081
2003 IG20, a MADD splice variant, increases cell susceptibility to gamma-irradiation and induces soluble mediators that suppress tumor cell growth. Cancer research 16 14695193
2021 CircRNA_0000429 Regulates Development of NSCLC by Acting as a Sponge of miR-1197 to Control MADD. Cancer management and research 15 33542659
2016 MADD-FOLH1 Polymorphisms and Their Haplotypes with Serum Lipid Levels and the Risk of Coronary Heart Disease and Ischemic Stroke in a Chinese Han Population. Nutrients 15 27070640
2001 Multiple acyl-CoA-dehydrogenase deficiency (MADD): use of acylcarnitines and fatty acids to monitor the response to dietary treatment. Pediatric research 15 11420420
2017 miR-181 interacts with signaling adaptor molecule DENN/MADD and enhances TNF-induced cell death. PloS one 14 28323882
2014 EVA-1 functions as an UNC-40 Co-receptor to enhance attraction to the MADD-4 guidance cue in Caenorhabditis elegans. PLoS genetics 13 25122090
2012 Mutations at the flavin binding site of ETF:QO yield a MADD-like severe phenotype in Drosophila. Biochimica et biophysica acta 13 22580358
2021 Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder. European journal of human genetics : EJHG 12 33723354
2021 Mechanistic insights into TNFR1/MADD death domains in Alzheimer's disease through conformational molecular dynamic analysis. Scientific reports 12 34112868
2014 MADD is a downstream target of PTEN in triggering apoptosis. Journal of cellular biochemistry 12 24038283
2011 Decreased oxidative phosphorylation and PGAM deficiency in horses suffering from atypical myopathy associated with acquired MADD. Molecular genetics and metabolism 12 21843962
2020 Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD) in the ETFDH gene: A case report and a literature review. Medicine 11 32925727
2013 Down-modulation of expression, or dephosphorylation, of IG20/MADD in tumor necrosis factor-related apoptosis-inducing ligand-resistant thyroid cancer cells makes them susceptible to treatment with this ligand. Thyroid : official journal of the American Thyroid Association 11 22998497
2012 Pregnancy of a patient with multiple Acyl-CoA dehydrogenation deficiency (MADD). Molecular genetics and metabolism 11 22664151
2011 Multiple acyl-CoA-dehydrogenase deficiency (MADD)--a novel mutation of electron-transferring-flavoprotein dehydrogenase ETFDH. Journal of the neurological sciences 11 21616504
2005 Clinical significance and neuropathology of primary MADD in C34-T and G468-T mutations of the AMPD1 gene. Clinical neuropathology 11 15803807
2024 MADD-like pattern of acylcarnitines associated with sertraline use. Molecular genetics and metabolism reports 10 39318848
2020 The Ig-like domain of Punctin/MADD-4 is the primary determinant for interaction with the ectodomain of neuroligin NLG-1. The Journal of biological chemistry 10 32928959
2014 Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. Circulation. Cardiovascular genetics 10 24951664
2021 Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at Caenorhabditis elegans neuromuscular junctions. Genetics 8 33983408
2021 Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity. JIMD reports 8 34485012
2016 The MADD-3 LAMMER Kinase Interacts with a p38 MAP Kinase Pathway to Regulate the Display of the EVA-1 Guidance Receptor in Caenorhabditis elegans. PLoS genetics 8 27123983
2012 The Caenorhabditis elegans homolog of the Opitz syndrome gene, madd-2/Mid1, regulates anchor cell invasion during vulval development. Developmental biology 8 23201576
2020 Correlation between ETFDH mutations and dysregulation of serum myomiRs in MADD patients. European journal of translational myology 7 32499892
2009 [Multiple acyl-CoA dehydrogenase deficiency (MADD): a curable cause of genetic muscular lipidosis]. Revue neurologique 7 19592060
2021 Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review. Frontiers in pediatrics 6 34041209
2021 Role of RNA in Molecular Diagnosis of MADD Patients. Biomedicines 6 34064479
2019 MADD silencing enhances anti-tumor activity of TRAIL in anaplastic thyroid cancer. Endocrine-related cancer 6 30999276
2013 MADD promotes the survival of human lung adenocarcinoma cells by inhibiting apoptosis. Oncology reports 5 23443411
2012 DENN/MADD/IG20 alternative splicing changes and cell death in Alzheimer's disease. Journal of molecular neuroscience : MN 5 22678883
2003 Molecular cloning, structural analysis, and expression of a human IRLB, MYC promoter-binding protein: new DENN domain-containing protein family emerges. Genomics 5 12906859
2024 MADD regulates natural killer cell degranulation through Rab27a activation. Journal of cell science 4 38506245
2024 A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes. JCI insight 4 38775154
2023 CaSR links endocytic and secretory pathways via MADD, a Rab11A effector that activates Rab27B. Cellular signalling 4 37604243
2021 Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series. Frontiers in neurology 4 34819910
2019 MADD Expression in Lung Adenocarcinoma and its Impact on Proliferation and Apoptosis of Lung Adenocarcinoma Cells. Combinatorial chemistry & high throughput screening 4 30947659
2015 TRAIL suppresses human breast cancer cell migration via MADD/CXCR7. Asian Pacific journal of cancer prevention : APJCP 4 25854358
2005 Purification and properties of Rab3 GEP (DENN/MADD). Methods in enzymology 4 16473592
2025 A novel cause of type 1 von Willebrand disease: impaired exocytosis of Weibel-Palade bodies due to biallelic MADD variants. Blood 3 40668965
2024 Clinical, biochemical, and genetic spectrum of MADD in a South African cohort: an ICGNMD study. Orphanet journal of rare diseases 3 38221620
2023 Calloso-adreno-scrotal agenesis associated with biallelic MAPK-activating death domain protein (MADD) variant: Further phenotypic delineation of MADD deficiency. American journal of medical genetics. Part A 3 37932938
2022 madd-4 plays a critical role in light against Bursaphelenchus xylophilus. Scientific reports 3 36042283
2020 Late-onset MADD in Yemen caused by a novel ETFDH mutation misdiagnosed as ADEM. Multiple sclerosis and related disorders 3 33383363
2017 Into the linker's DENN: A tyrosine's control of autophagy. The Journal of biological chemistry 3 28455410

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