Affinage

MADD

MAP kinase-activating death domain protein · UniProt Q8WXG6

Round 2 corrected
Length
1647 aa
Mass
183.3 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MADD is a multifunctional signaling adaptor and Rab GTPase exchange factor that integrates death receptor signaling with regulated exocytosis. Through its C-terminal death domain, MADD binds TNFR1 and TRAIL receptors DR4/DR5, where Akt-mediated phosphorylation controls its association with DR4 to block FADD recruitment and caspase-8 activation; dephosphorylation by PTEN-dependent mechanisms releases MADD to the cytoplasm, where it displaces Bax from 14-3-3 and triggers mitochondrial apoptosis (PMID:20484047, PMID:24038283, PMID:17314102). MADD simultaneously functions as the principal GDP/GTP exchange factor for Rab3A–D and Rab27A/B via its tripartite DENN domain, and this GEF activity is essential for Ca²⁺-dependent insulin secretion, von Willebrand factor release from Weibel-Palade bodies, cytokine secretion, and cytotoxic lymphocyte degranulation (PMID:16473592, PMID:24379354, PMID:34551092, PMID:38506245). Biallelic loss-of-function MADD variants cause a multisystem disorder encompassing defective ERK signaling, enhanced apoptosis, impaired vesicular trafficking, and endocrine dysfunction including diabetes, hypogonadotropic hypogonadism, and growth hormone deficiency (PMID:32761064, PMID:38775154).

Mechanistic history

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

    Identification of MADD as a TNFR1 death-domain interactor that activates MAP kinases established the first molecular link between TNF receptor signaling and ERK/JNK activation through a novel adaptor protein.

    Evidence Yeast two-hybrid screen followed by co-immunoprecipitation and overexpression kinase-activation assays in mammalian cells

    PMID:9115275

    Open questions at the time
    • Endogenous role not yet shown by loss-of-function
    • Mechanism connecting MADD to MAP kinase cascade unresolved
    • Physiological context (cell type specificity) unknown
  2. 2001 High

    Discovery that alternative splice variants (IG20 vs DENN-SV) exert opposing effects on TNF-α-induced caspase-8 activation revealed that the gene's apoptotic function is isoform-specific, resolving apparently contradictory pro- and anti-apoptotic reports.

    Evidence Stable transfection of individual splice variants with caspase activation assays and CrmA epistasis

    PMID:11577081

    Open questions at the time
    • Structural basis for isoform-specific effects unresolved
    • Endogenous isoform ratios in relevant tissues not defined
  3. 2004 High

    Demonstration that MADD interacts with TRAIL receptors DR4/DR5 and enhances DISC formation, while competing with TRADD for TNFR1 binding to suppress neuronal apoptosis, established MADD as a dual-receptor signaling node governing cell survival decisions at multiple death receptors.

    Evidence Co-immunoprecipitation of MADD-DR4/DR5 complexes, DISC assembly assays, competitive TNFR1 binding, and antisense knockdown in primary hippocampal neurons

    PMID:15007167 PMID:15208670

    Open questions at the time
    • How MADD distinguishes TNFR1 vs DR4/DR5 structurally unknown
    • Whether MADD competes with TRADD at endogenous expression levels unresolved
  4. 2005 High

    In vitro reconstitution of MADD/Rab3GEP GEF activity on all four lipid-modified Rab3 isoforms (but not unmodified Rab3 or Rab3-GDI complexes) defined the enzymatic specificity of the DENN domain, establishing MADD as a bona fide Rab3 GEF requiring membrane-anchored substrate.

    Evidence Purified recombinant Rab3GEP from Sf9 cells, in vitro GDP/GTP exchange assay with lipid modification controls

    PMID:16473592

    Open questions at the time
    • Crystal structure of DENN domain–Rab3 interface unavailable
    • Relative in vivo contribution to each Rab3 family member unresolved
  5. 2007 High

    Isoform-specific knockdown and rescue experiments established that the MADD isoform specifically is both necessary and sufficient for cancer cell survival by inhibiting caspase-8 activation at death receptors independently of FADD recruitment, defining MADD as a gatekeeper of extrinsic apoptosis.

    Evidence Exon-specific shRNA with shRNA-resistant rescue, co-IP showing MADD binds DR4/DR5 but not caspase-8 or FADD

    PMID:16682944 PMID:17314102

    Open questions at the time
    • Structural mechanism by which MADD blocks caspase-8 activation at the receptor unknown
    • Whether MADD acts stoichiometrically or catalytically at death receptors unresolved
  6. 2008 High

    Discovery that kinesin motors KIF1Bβ and KIF1A directly bind MADD/Rab3GEP, which in turn preferentially binds GTP-Rab3, established an axonal transport cascade (KIF1B→MADD→Rab3) coupling motor-driven vesicle transport to Rab3 nucleotide state.

    Evidence Yeast two-hybrid, co-immunoprecipitation, in vivo axonal transport assays in genetic knockout backgrounds

    PMID:18849981

    Open questions at the time
    • Whether MADD acts as a GEF during transport or only as an effector/adaptor unresolved
    • Cargo identity on KIF1B-MADD-Rab3 vesicles not fully defined
  7. 2009 High

    Endogenous MADD knockdown specifically abolished TNF-α-induced ERK1/2 (but not JNK, p38, or NF-κB) activation by disrupting Grb2/Sos1-2 recruitment to TNFR1 and downstream Ras/MEKK activation, mapping the precise signaling branch controlled by MADD.

    Evidence Lentiviral shRNA knockdown with rescue, co-IP of TNFR1 signaling complex, Ras-GTP pull-down

    PMID:19289468

    Open questions at the time
    • How MADD recruits Grb2 mechanistically (direct or indirect interaction) not defined
    • Whether this ERK-specific branch operates in non-immune cell types unresolved
  8. 2010 High

    Identification of three Akt phosphorylation sites on MADD that control its DR4 binding and anti-apoptotic function, and expansion of its GEF substrate range to include Rab27A/B, integrated MADD into both PI3K/Akt survival signaling and lysosomal/secretory granule trafficking.

    Evidence Phosphosite mapping by mass spectrometry/mutagenesis with constitutively active and dominant-negative Akt epistasis; systematic DENN-domain GEF screen for Rab specificity

    PMID:20484047 PMID:20937701

    Open questions at the time
    • Phosphatase(s) that dephosphorylate MADD at these sites not identified beyond PTEN pathway
    • Relative importance of Rab3 vs Rab27 GEF activity in different tissues unclear
  9. 2013 High

    Conditional knockout of MADD in pancreatic β-cells caused severe glucose-stimulated insulin secretion defects and hyperglycemia without impairing insulin processing, providing the first in vivo genetic proof that MADD's vesicle exocytosis function is physiologically essential for endocrine secretion.

    Evidence Beta-cell-specific conditional knockout mouse, glucose tolerance tests, insulin accumulation and secretion assays

    PMID:24379354

    Open questions at the time
    • Whether Rab3 or Rab27 GEF activity mediates insulin secretion not dissected
    • Potential compensatory changes in other DENN-domain GEFs not assessed
  10. 2014 High

    Elucidation of the PTEN-MADD-14-3-3-Bax axis showed that dephosphorylated MADD translocates from the membrane to cytoplasm and displaces Bax from 14-3-3, activating mitochondrial apoptosis, linking MADD phosphorylation status to intrinsic apoptosis in addition to extrinsic pathway regulation.

    Evidence Subcellular fractionation, co-IP of MADD/14-3-3/Bax, cytochrome c release assay, PTEN siRNA epistasis

    PMID:24038283

    Open questions at the time
    • Whether this pathway operates in non-cancer cell types unknown
    • Direct demonstration that dephosphorylated MADD physically contacts 14-3-3 at endogenous levels not shown
  11. 2020 High

    Characterization of patient-derived fibroblasts from 23 individuals with biallelic MADD variants confirmed that MADD deficiency simultaneously impairs TNF-α-induced ERK activation, increases caspase-dependent apoptosis, and disrupts EGF receptor endocytosis, validating the dual signaling-trafficking model in a human disease context.

    Evidence Patient fibroblasts with confirmed MADD protein loss, ERK phosphorylation, caspase-3/7 assay, EGF internalization assay

    PMID:32761064

    Open questions at the time
    • Specific Rab substrates affected in patient cells not identified
    • Whether vesicular trafficking defect is Rab3- or Rab27-dependent not distinguished
  12. 2021 High

    Demonstration that MADD's DENN-domain GEF activity (not mere Rab binding) is required for Rab27A/Rab3B/Rab3D recruitment to Weibel-Palade bodies and VWF secretion in endothelial cells, and that cytosolic localization of MADD is essential, resolved whether catalytic activation or scaffolding drives Rab targeting.

    Evidence siRNA knockdown, Rab-GTP activity assay, DENN-domain mutant, MADD-TOMM70 mistargeting construct, VWF secretion assay

    PMID:34551092

    Open questions at the time
    • How MADD is recruited to specific vesicle populations remains unknown
    • Whether MADD GEF activity is regulated by phosphorylation at vesicle membranes not tested
  13. 2024 High

    MADD knockout in NK cells established that MADD is the principal Rab27a GEF controlling cytotoxic lymphocyte degranulation and killing, activating Rab27a without being required for lytic granule docking at the synapse, dissecting activation from tethering functions.

    Evidence Genetic knockout, GTP-Rab27a pull-down, degranulation and cytolysis assays, immunofluorescence at the cytolytic synapse

    PMID:38506245

    Open questions at the time
    • Post-activation Rab27a effectors downstream of MADD in NK cells not identified
    • Whether other DENN-domain GEFs partially compensate not assessed
  14. 2024 High

    Analysis of patients carrying an in-frame MADD exon-30 deletion showed that the mutant protein retains GEF activity but has altered protein-protein interactions, causing diabetes, hypogonadotropic hypogonadism, and GH deficiency, revealing that MADD's non-catalytic interactions are essential for endocrine function independently of GEF activity.

    Evidence Patient genetics, hESC-derived islets, EndoC-βH1, LβT2 gonadotrope cells, GEF activity assay, protein-protein interaction proteomics

    PMID:38775154

    Open questions at the time
    • Specific interactors lost in the dex30 mutant that drive endocrine phenotypes not identified
    • Whether dex30 affects death-domain-mediated signaling not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MADD's GEF, death-domain, and scaffolding functions are coordinated in space and time — and which are affected in specific disease contexts — remains unresolved.
  • No high-resolution structure of full-length MADD or DENN–Rab complex available
  • Whether phosphorylation-dependent membrane/cytoplasm shuttling regulates GEF activity in addition to apoptotic signaling is untested
  • Tissue-specific isoform expression ratios and their functional consequences are incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 6 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-168256 Immune System 2
Partners
GRB2KIF1BRAB11ARAB27ARAB3ATNFRSF10ATNFRSF10BTNFRSF1A

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MADD (MAP kinase-activating death domain protein) was identified as a novel protein that associates with the death domain of TNFR1 through its own C-terminal death domain, as demonstrated by yeast two-hybrid and co-immunoprecipitation. Overexpression of MADD activates the MAP kinase ERK, and expression of the MADD death domain stimulates both ERK and JNK MAP kinases and induces phosphorylation of cytosolic phospholipase A2, linking TNFR1 to MAP kinase activation and arachidonic acid release. Yeast two-hybrid, co-immunoprecipitation, overexpression with ERK/JNK kinase activation assays The Journal of biological chemistry High 9115275
1996 DENN (identical/highly similar to MADD) was identified as a novel human gene encoding a 1287 aa hydrophilic protein with predominant cell membrane localization and some cytoplasmic staining, as shown by immunofluorescent labeling. Western blotting confirmed a 140–145 kDa protein product. An alternative splicing event involving a 129 nt exon was identified. Western blotting, immunofluorescence localization, Northern blot, RACE cDNA cloning DNA sequence : the journal of DNA sequencing and mapping Medium 8988362
1998 The DENN gene (virtually identical to MADD) was mapped to chromosome 11p11.21-p11.22 by FISH, comprises 15 exons and 14 introns spanning ~28 kb, and alternative splicing generates two protein isoforms differentially expressed in cells of different lineages. The DENN/MADD protein shows homology to rat Rab3 GEP (a Rab3 GDP/GTP exchange protein) and to C. elegans AEX-3, which interacts with Rab3 to regulate synaptic vesicle release. FISH, genomic sequencing, Western blotting of subcellular fractions, RT-PCR Genome Medium 9796103
2001 IG20 (MADD splice variant) and DENN-SV (another splice variant of the same gene) exert opposing effects on TNF-alpha-induced apoptosis. All variants interact with TNFR1 and activate ERK and NF-kappaB. However, only IG20-expressing cells show enhanced TNF-alpha-induced caspase-8 and caspase-3 activation, while DENN-SV-expressing cells show reduced or no caspase activation. CrmA maximally inhibited apoptosis in IG20 cells, establishing caspase-8 dependence. Stable transfection, TNF-alpha treatment, caspase activation assays, co-immunoprecipitation with TNFR1, CrmA inhibitor experiments The Journal of biological chemistry High 11577081
2001 The DENN domain is structurally larger than previously annotated and is flanked on both sides by conserved domains termed uDENN and dDENN, forming a tripartite module. This tripartite DENN module is present in MADD (MAP kinase activating death domain protein) and other signaling proteins interacting with Rab GTPases or regulating MAPK pathways. Computational profile-based and bidimensional sequence analysis Biochemical and biophysical research communications Low 11563850
2002 Antisense silencing of DENN/MADD expression in cancer cell lines (Jurkat, PLC/PRF/5, NS-1) induced marked apoptosis, while DENN/MADD overexpression augmented cellular proliferation and reversed apoptotic effects of antisense treatment or staurosporine, establishing an anti-apoptotic and cell-survival role for DENN/MADD. Antisense oligodeoxynucleotide treatment, flow cytometry (annexin V, TUNEL, sub-G1), overexpression rescue, electron microscopy Molecular carcinogenesis Medium 12410563
2004 DENN/MADD protein expression is significantly reduced in Alzheimer's disease (AD) hippocampus and brain homogenates relative to controls. DENN/MADD and TRADD competitively bind TNFR1 when overexpressed in N2A cells, with DENN/MADD abrogating TNFR1 binding to TRADD. Antisense reduction of endogenous DENN/MADD in rat hippocampal neurons promoted neuronal cell death, indicating DENN/MADD is protective by preventing TRADD-mediated apoptotic signaling. Immunohistochemistry, Western blotting of brain homogenates, antisense knockdown in primary hippocampal neurons, co-immunoprecipitation competition assay in N2A cells Proceedings of the National Academy of Sciences of the United States of America High 15007167
2004 IG20 (pro-apoptotic splice variant of the MADD/IG20 gene) interacts directly with TRAIL death receptors DR4 and DR5, and increases recruitment of FADD and caspase-8 into the TRAIL death-inducing signaling complex (DISC), thereby enhancing TRAIL-induced apoptosis via caspase activation. Colocalization, co-immunoprecipitation of DR4/DR5 with IG20, DISC assembly assay, caspase inhibitors (p35, CrmA, DN-FADD) Oncogene High 15208670
2004 DENN/MADD (Rab3GEP) regulates the recycling of Rab3 small G proteins and has an essential role in Ca2+-dependent neurotransmitter release and exocytosis. It is also involved in blocking neuronal cell apoptosis under cytotoxic stress conditions through its interactions with TNFR1 and JNK3. Review synthesizing prior biochemical and cellular studies Trends in molecular medicine Medium 15464446
2004 Antisense abrogation of DENN/MADD expression in K36 leukemia cells induced apoptosis in vitro and caused tumor regression in vivo. In NFkappaB and TNFR1 knockout cells, antisense treatment caused more pronounced cell death, while TNFalpha and TNFR2 knockouts showed less apoptosis. DENN overexpression stimulated cell proliferation and upregulated TRPM2 and cyclin B1. Antisense treatment altered expression of TNFR2, TRAIL, Fas, TNFalpha, and cyclin D3, placing DENN/MADD in an apoptotic-cell cycle regulatory network. Antisense oligonucleotide treatment, knockout cell lines, in vivo tumor model, flow cytometry, RT-PCR expression arrays International journal of cancer Medium 14735464
2005 Recombinant Rab3 GEP (DENN/MADD) purified from Sf9 cells acts as a GDP/GTP exchange factor active on lipid-modified Rab3A, -3B, -3C, and -3D, but is inactive on lipid-unmodified Rab3A or Rab3A complexed with Rab GDI. Overexpression of Rab3 GEP inhibits Ca2+-dependent exocytosis from PC12 cells. In vitro GDP/GTP exchange assay with purified recombinant protein, lipid modification requirement test, Rab GDI inhibition assay, PC12 cell overexpression exocytosis assay (human growth hormone coexpression assay) Methods in enzymology High 16473592
2006 Selective knockdown of MADD (but not other IG20 splice variants) using exon-specific shRNA renders HeLa and PA-1 cancer cells susceptible to spontaneous apoptosis without affecting cell proliferation or cell cycle. Re-expression of MADD alone (not DENN-SV) in the absence of endogenous IG20 splice variants was sufficient to rescue cells from spontaneous apoptosis, establishing MADD as necessary and sufficient for cancer cell survival. Exon-specific shRNA knockdown, rescue with shRNA-resistant MADD expression, flow cytometry apoptosis assay Oncogene High 16682944
2007 Endogenous 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. MADD knockdown leads to caspase-8 activation without increased FADD recruitment, indicating MADD inhibits caspase-8 activation downstream of DISC assembly. Exon-specific shRNA, immunoprecipitation showing MADD-DR interaction but not MADD-caspase-8 or MADD-FADD, caspase-8 activation assay, CrmA and DN-FADD epistasis The Journal of biological chemistry High 17314102
2008 KIF1Bbeta and KIF1A motors interact directly with DENN/MADD (Rab3-GEP) through the stalk domain. DENN/MADD binds preferentially to GTP-Rab3 (acting as a Rab3 effector in addition to its GEF role). Sequential genetic perturbations showed KIF1Bbeta and KIF1A are essential for transport of DENN/MADD and Rab3, while DENN/MADD is essential for Rab3 transport. GTP-Rab3 is more effectively transported than GDP-Rab3, indicating nucleotide state regulates axonal transport through preferential interaction with DENN/MADD. Yeast two-hybrid, co-immunoprecipitation, in vivo axonal transport assays with genetic knockouts, GTP/GDP-Rab3 binding preference assay Nature cell biology High 18849981
2008 Neural-enriched IG20 splice isoforms KIAA0358 and IG20-SV4 are expressed in human neuroblastoma cells and neural tissues. KIAA0358 exerts a potent antiapoptotic effect while IG20-SV4 has proapoptotic effects directly related to caspase-8 activation in neuroblastoma cells with minimal constitutive caspase-8 expression. Gain-of-function transfection, siRNA knockdown, caspase-8 activation assay, flow cytometry Cancer research Medium 18794122
2009 Endogenous MADD is indispensable for TNF-alpha-induced activation of MAPK (ERK1/2) but not for NF-kappaB activation, JNK or p38. MADD knockdown reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation. Re-expression of shRNA-resistant MADD rescued cells from TNF-alpha-induced apoptosis, establishing the Grb2/Sos1-2/Ras/MEKK pathway as downstream of MADD. Exon-specific shRNA lentiviral knockdown, pathway activation assays (ERK, JNK, p38, NF-kappaB), co-immunoprecipitation of TNFR1 complex components, Ras activation assay, rescue by re-expression The Journal of biological chemistry High 19289468
2010 Akt phosphorylates endogenous MADD at three conserved sites. Only phosphorylated MADD can directly interact with the TRAIL receptor DR4, thereby preventing FADD recruitment. TRAIL treatment reduces MADD phosphorylation levels in sensitive cells, causing MADD dissociation from DR4 and allowing DISC formation and apoptosis. Constitutively active Akt rendered TRAIL-sensitive cells resistant; dominant-negative Akt in resistant cells reduced pMADD and sensitized them to TRAIL. Phosphorylation site mapping (mass spectrometry/mutagenesis), co-immunoprecipitation of pMADD-DR4 interaction, constitutively active and dominant-negative Akt overexpression, TRAIL-induced apoptosis assay The Journal of biological chemistry High 20484047
2010 MADD is a GDP/GTP exchange factor (GEF) that activates Rab27A and Rab27B, as part of a systematic characterization of the 17 human DENN domain proteins assigning specific Rab substrates. Systematic GEF activity screen, localization assays The Journal of cell biology Medium 20937701
2012 Alternative splicing changes in DENN/MADD/IG20 (DMI) occur in Alzheimer's disease brains and in SH-SY5Y cells exposed to oligomeric Abeta. Initially, the ratio of DM-SV to IG20 increases in cultures exposed to oAbeta. Knockdown of DMI splice variants including DM-SV with antisense increased cell death, while siRNAs sparing DM-SV increased the DM-SV/IG20 ratio and reduced cell death, suggesting DM-SV (MADD) is required for neuronal survival against oAbeta toxicity. Antisense DNA knockdown, isoform-specific siRNA, cell viability assay, RT-PCR quantification of splice variant ratios in AD and control brain tissue Journal of molecular neuroscience : MN Medium 22678883
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 IPR-induced amylase release and reduced GTP-Rab27 levels in streptolysin O-permeabilized cells, indicating MADD's GEF activity (GDP/GTP cycling on Rab27) is required for stimulated exocytosis. Antibody inhibition in permeabilized cells, GTP-Rab27 pull-down assay, amylase release measurement, RT-PCR for DENND family expression Archives of biochemistry and biophysics Medium 23702376
2013 Conditional knockout of IG20/MADD in pancreatic beta-cells (KMA1ko mice) resulted in hyperglycemia, glucose intolerance, and a severe defect in glucose-induced insulin release without defects in insulin processing. KMA1ko beta-cells showed increased insulin accumulation, indicating MADD plays a critical role in insulin secretion (vesicle exocytosis) from beta-cells. Conditional knockout mouse model, glucose tolerance testing, insulin secretion assay, insulin processing/accumulation measurement Diabetes High 24379354
2014 MADD acts as a downstream target of PTEN in TRAIL-induced apoptosis. TRAIL induces reduction of MADD phosphorylation via PTEN upregulation; PTEN knockdown prevented TRAIL-induced reduction in pMADD. Non-phosphorylated MADD translocates from the plasma membrane to the cytoplasm where it binds 14-3-3 and displaces 14-3-3-associated Bax, causing Bax translocation to mitochondria and cytochrome c release. PTEN siRNA knockdown, subcellular fractionation, co-immunoprecipitation of MADD/14-3-3/Bax, mitochondrial cytochrome c release assay, subcellular localization by immunofluorescence Journal of cellular biochemistry High 24038283
2015 miR-3151 directly targets MADD (confirmed by luciferase assay) and PIK3R2. Restoration of miR-3151 in CLL cells repressed MADD expression, downregulated MEK/ERK signaling, inhibited proliferation, and enhanced apoptosis, placing MADD as a direct upstream activator of MEK/ERK in CLL cells. Luciferase reporter assay, miRNA re-expression, Western blotting for MADD/ERK/AKT, cell proliferation and apoptosis assays Oncotarget Medium 26517243
2017 miR-181 binds the 3' UTR of DENN/MADD transcripts (validated by luciferase reporter assay) and reduces endogenous DENN/MADD mRNA levels. miR-181 overexpression accentuates mitochondrial membrane potential loss and enhances apoptosis in TNF-alpha-treated L929 cells, linking DENN/MADD suppression to enhanced TNF-alpha pro-death signaling. Luciferase 3'UTR reporter assay, miRNA overexpression, endogenous mRNA quantification, mitochondrial membrane potential assay, flow cytometry apoptosis PloS one Medium 28323882
2019 MADD knockdown in anaplastic thyroid cancer cells inhibited proliferation, migration, invasion, and clonogenic capacity, and reduced mitochondrial length and potential. Mechanistically, MADD siRNA inhibited TNFalpha-induced pERK, pGSK3beta, and beta-catenin nuclear translocation, placing MADD upstream of the TNFalpha/ERK/GSK3beta/Wnt axis in ATC. In vivo orthotopic mouse model confirmed tumor regression and decreased lung metastases. siRNA knockdown, proliferation/invasion/migration assays, mitochondrial function assay, Western blotting for signaling, in vivo orthotopic mouse model Cell death & disease Medium 30760700
2020 Biallelic MADD variants in patients result in loss of MADD protein. Patient-derived fibroblasts show reduced ERK1/2 phosphorylation upon TNF-alpha treatment, enhanced caspase-3/7 activation, increased apoptosis, and defective EGF receptor endocytosis, establishing that MADD deficiency causes simultaneous defects in TNF-alpha-dependent MAPK signaling and vesicular trafficking. Patient fibroblasts from 23 individuals with MADD variants, Western blotting for MADD protein, TNF-alpha stimulation with ERK phosphorylation assay, caspase-3/7 activity assay, EGF internalization assay, mRNA splice variant analysis Brain : a journal of neurology High 32761064
2021 MADD acts as the GDP/GTP exchange factor for Rab27A, Rab3B, and Rab3D in primary human endothelial cells. Rab activity assays showed reduced Rab27A, Rab3B, and Rab3D activation upon MADD silencing. DENN domain-dependent GEF activity (not mere binding) was required for Rab recruitment to Weibel-Palade bodies (WPBs). Artificial mistargeting of MADD abolished Rab27A localization to WPBs in a DENN domain-dependent manner, indicating cytosolic MADD localization is critical. MADD silencing reduced VWF intracellular content and decreased histamine-evoked VWF secretion. siRNA knockdown, Rab activity (GTP-loading) assay, immunofluorescence localization, MADD-TOMM70 mistargeting construct, DENN domain mutant, VWF secretion assay Blood advances High 34551092
2021 A homozygous splice-site variant in MADD (c.2816+1G>A) causes single exon skipping and out-of-frame deletion, resulting in an infantile-lethal syndrome. MADD encodes a Rab GEF that activates RAB3 and RAB27A/27B and is crucial for neuromuscular junction function and endocrine secretory granule release, and also protects cells from caspase-mediated TNF-alpha-induced apoptosis. Exome sequencing, cDNA analysis confirming exon skipping, segregation analysis, clinical phenotype correlation European journal of human genetics : EJHG Medium 33723354
2023 CaSR stimulation drives Rab11A-dependent activation of MADD (a Rab11A effector), which then activates Rab27B-regulated secretion of IL-8, CCL2/MCP-1, IL-1beta, and attenuates IL-6 secretion. Rab11A co-immunoprecipitates with MADD, and endosomal PI3-kinases (Vps34 and PI3KC2alpha) promote MADD/Rab27B pathway activation, linking endocytic recycling endosomes to secretory vesicles via MADD. Co-immunoprecipitation of Rab11A-MADD, PI3K inhibitors, siRNA knockdown of pathway components, secretion assay for cytokines, Rab27B activation assay Cellular signalling Medium 37604243
2023 AML blast-derived exosomes transfer miR-24-3p to T cells, where it directly targets DENN/MADD (validated by direct targeting assay) and alters NF-kappaB, p-JAK/STAT, and p-ERK signaling pathways, increasing T-cell apoptosis and promoting regulatory T-cell development. miR-24-3p overexpression decreased DENN/MADD expression and impaired T-cell function. Exosome transfer experiments, miRNA overexpression, DENN/MADD expression knockdown, flow cytometry for apoptosis, NF-kappaB/JAK-STAT/ERK signaling assays, direct targeting assay Cell communication and signaling : CCS Medium 37735672
2024 MADD knockout in natural killer cells significantly decreased GTP-bound Rab27a levels in both resting and stimulated NK cells. MADD-deficient NK cells and CD8+ T cells displayed severely reduced degranulation and cytolytic ability comparable to Rab27a deficiency. Although MADD colocalized with Rab27a on lytic granules (LGs) and was enriched at the cytolytic synapse, loss of MADD did not impair Rab27a association with LGs nor their recruitment to the synapse, indicating MADD specifically activates Rab27a without controlling LG docking. MADD knockout (genetic), GTP-Rab27a pull-down activity assay, degranulation assay, cytolysis assay, immunofluorescence colocalization on lytic granules, synapse recruitment assay Journal of cell science High 38506245
2024 Nucleolin (NCL) is lactylated predominantly at lysine 477 by the acyltransferase P300 in response to hyperactive glycolysis. Lactylated NCL binds the primary transcript of MADD and promotes efficient translation of MADD by circumventing alternative splicing that would otherwise generate a premature termination codon. This NCL lactylation-driven MADD upregulation activates ERK signaling to drive intrahepatic cholangiocarcinoma development. Proteomics of clinical specimens, mass spectrometry of lactylation sites, P300 acyltransferase identification, RNA binding assay (NCL-MADD pre-mRNA), alternative splicing analysis, xenograft tumor model Journal of hepatology High 38679071
2024 A homozygous MADD splice site variant causing skipping of exon 30 (in-frame deletion of 36 amino acids, dex30) in patients with diabetes, hypogonadotropic hypogonadism, and growth hormone deficiency reduces insulin content, increases proinsulin-to-insulin ratio, decreases beta-cell numbers in stem cell-derived islets, and decreases luteinizing hormone expression in pituitary gonadotrope cells. The dex30 protein retained intact GDP/GTP exchange activity but showed altered protein-protein interaction profiles affecting multiple signaling pathways. Patient genetic analysis, MADD exon 30 deletion in hESC-derived pancreatic islets and human beta-cell line EndoC-βH1 and mouse LβT2 gonadotrope cells, insulin/proinsulin content assays, LH expression assay, GDP/GTP exchange activity assay, protein-protein interaction proteomics JCI insight High 38775154

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
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