Affinage

SAMD4A

Protein Smaug homolog 1 · UniProt Q9UPU9

Length
718 aa
Mass
79.4 kDa
Annotated
2026-04-28
100 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SAMD4A (mammalian Smaug1) is an RNA-binding translational repressor that recognizes Smaug recognition element (SRE) stem-loop structures in target mRNA 3' UTRs through its SAM domain, leading to translational silencing and mRNA destabilization; it forms cytoplasmic mRNP granules and is enriched in neuronal post-synaptic densities (PMID:16221671). SAMD4A directly destabilizes proangiogenic transcripts including CXCL5, ENG, IL1β, and ANGPT1, thereby suppressing tumor angiogenesis in breast cancer (PMID:34219323). SAMD4A also physically interacts with CUGBP1 in human myoblasts, correcting its aberrant nuclear accumulation and restoring CUGBP1-dependent translation in myotonic dystrophy type 1 (DM1) patient cells (PMID:23637619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2005 Medium

    Establishing that mammalian SAMD4A functions as an SRE-dependent translational repressor and forms cytoplasmic mRNP granules enriched in neuronal synapses resolved the question of whether Drosophila Smaug function is conserved in mammals.

    Evidence Overexpression in fibroblasts, in vitro translation reporter assays, immunofluorescence, and biochemical fractionation of murine brain tissue

    PMID:16221671

    Open questions at the time
    • Endogenous mammalian mRNA targets of SAMD4A were not identified
    • Mechanism of mRNP granule formation and its relationship to translational repression was not dissected
    • No loss-of-function studies in neurons
  2. 2013 Medium

    Demonstrating that SAMD4A physically interacts with CUGBP1 and rescues its mislocalization and translational defects in DM1 myoblasts established SAMD4A as a modulator of CUGBP1-dependent translation with disease relevance.

    Evidence Co-immunoprecipitation, overexpression/knockdown in human myoblasts, translation assays for MRG15 target

    PMID:23637619

    Open questions at the time
    • Whether SAMD4A directly binds CUGBP1 or acts through an RNA intermediate was not resolved
    • Therapeutic relevance in DM1 animal models was not tested
    • Whether the SAMD4A-CUGBP1 axis operates outside myoblasts is unknown
  3. 2021 Medium

    Showing that SAMD4A directly binds stem-loop structures in the 3' UTRs of proangiogenic mRNAs via its SAM domain and destabilizes them provided the first identification of endogenous mammalian target transcripts and linked SAMD4A to tumor angiogenesis suppression.

    Evidence RNA-binding assays with SAM domain, mRNA stability measurements, overexpression/knockdown in breast cancer cells and xenograft models

    PMID:34219323

    Open questions at the time
    • Genome-wide identification of SAMD4A direct targets (e.g., by CLIP) has not been performed
    • Whether mRNA destabilization involves deadenylation machinery (as in Drosophila Smaug) is untested in mammalian cells
    • Structural basis of SAM domain–stem-loop recognition is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full spectrum of endogenous SAMD4A mRNA targets, the molecular mechanism linking SRE binding to mRNA decay (e.g., deadenylase recruitment), the structural determinants of SAM domain–RNA recognition, and the in vivo physiological roles of SAMD4A in the nervous system.
  • No transcriptome-wide target map (CLIP-seq) exists for mammalian SAMD4A
  • No structural model of the SAM domain bound to an SRE stem-loop
  • In vivo neuronal loss-of-function phenotypes have not been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0045182 translation regulator activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
CUGBP1ELAVL1STAU1TIA1TIAR

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Mammalian SAMD4A (hSmaug1) acts as a translational repressor of reporter transcripts carrying Smaug recognition element (SRE) motifs and forms cytoplasmic granules containing polyadenylated mRNA and RNA-binding proteins Staufen, TIAR, TIA-1, and HuR; murine Smaug1 is expressed in the central nervous system, is abundant in post-synaptic densities, and is present in synaptoneurosomal 20S particles. Overexpression in fibroblasts, in vitro translation reporter assays, immunofluorescence, biochemical fractionation The Journal of biological chemistry Medium 16221671
2013 Human SAMD4A (SMAUG1) physically interacts with CUGBP1 in human myoblasts, and increased SAMD4A levels correct abnormal nuclear accumulation of CUGBP1 in DM1 patient myoblasts, reduce inactive CUGBP1-eIF2α translational complexes, and restore translation of MRG15 (a CUGBP1 downstream target), demonstrating a role for SAMD4A in regulating CUGBP1 translational activity. Co-immunoprecipitation, overexpression/knockdown in human myoblasts, translation assays, immunofluorescence PLoS genetics Medium 23637619
2021 SAMD4A directly destabilizes proangiogenic mRNA transcripts (CXCL5, ENG, IL1β, ANGPT1) by binding to stem-loop structures in their 3' UTRs through its SAM domain, thereby inhibiting breast tumor angiogenesis; overexpression inhibited angiogenesis and tumor progression whereas knockdown reversed this effect. RNA-binding assay (SAM domain), mRNA stability assay, overexpression/knockdown in breast cancer cells and xenograft models Cancer science Medium 34219323
2020 The circular RNA derived from the SAMD4A locus (circSAMD4A) acts as a miR-138-5p sponge, thereby increasing EZH2 expression and promoting preadipocyte differentiation; circSAMD4A knockdown reversed HFD-induced obesity phenotypes in mice. circRNA overexpression/knockdown in vitro and in vivo (HFD mice), luciferase reporter assay for miRNA sponge activity Theranostics Medium 32292524

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 mRNA surveillance by the Caenorhabditis elegans smg genes. Genes & development 420 8104846
1993 Rabphilin-3A, a putative target protein for smg p25A/rab3A p25 small GTP-binding protein related to synaptotagmin. Molecular and cellular biology 378 8384302
2001 Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes & development 331 11544179
1990 Purification and characterization from bovine brain cytosol of a protein that inhibits the dissociation of GDP from and the subsequent binding of GTP to smg p25A, a ras p21-like GTP-binding protein. The Journal of biological chemistry 275 2105320
2007 SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase. Developmental cell 265 17199047
1990 Regulation of reversible binding of smg p25A, a ras p21-like GTP-binding protein, to synaptic plasma membranes and vesicles by its specific regulatory protein, GDP dissociation inhibitor. The Journal of biological chemistry 244 2115887
1991 A stimulatory GDP/GTP exchange protein for smg p21 is active on the post-translationally processed form of c-Ki-ras p21 and rhoA p21. Proceedings of the National Academy of Sciences of the United States of America 223 1907371
2005 Smaug recruits the CCR4/POP2/NOT deadenylase complex to trigger maternal transcript localization in the early Drosophila embryo. Current biology : CB 210 15723788
2003 Drosophila Cup is an eIF4E-binding protein that functions in Smaug-mediated translational repression. The EMBO journal 210 14685270
2001 Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Molecular and cellular biology 207 11113196
1996 smaug protein represses translation of unlocalized nanos mRNA in the Drosophila embryo. Genes & development 203 8895661
1999 SMG-2 is a phosphorylated protein required for mRNA surveillance in Caenorhabditis elegans and related to Upf1p of yeast. Molecular and cellular biology 199 10454541
2009 SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes & development 198 19417104
1999 Smaug, a novel RNA-binding protein that operates a translational switch in Drosophila. Molecular cell 194 10488336
1991 C terminus of the small GTP-binding protein smg p25A contains two geranylgeranylated cysteine residues and a methyl ester. Proceedings of the National Academy of Sciences of the United States of America 194 1906176
2003 The RNA-binding SAM domain of Smaug defines a new family of post-transcriptional regulators. Nature structural biology 183 12858164
1990 Localization and subcellular distribution of smg p25A, a ras p21-like GTP-binding protein, in rat brain. The Journal of biological chemistry 161 2114404
1990 Posttranslationally processed structure of the human platelet protein smg p21B: evidence for geranylgeranylation and carboxyl methylation of the C-terminal cysteine. Proceedings of the National Academy of Sciences of the United States of America 161 2123345
2006 Oskar allows nanos mRNA translation in Drosophila embryos by preventing its deadenylation by Smaug/CCR4. Development (Cambridge, England) 159 17050620
1990 Molecular cloning and characterization of a novel type of regulatory protein (GDI) for smg p25A, a ras p21-like GTP-binding protein. Molecular and cellular biology 149 2115118
1993 Two functionally different domains of rabphilin-3A, Rab3A p25/smg p25A-binding and phospholipid- and Ca(2+)-binding domains. The Journal of biological chemistry 136 8262955
2001 Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein. The Journal of biological chemistry 133 11331269
1999 Smaug, a novel and conserved protein, contributes to repression of nanos mRNA translation in vitro. RNA (New York, N.Y.) 123 10606265
2003 SMG-5, required for C.elegans nonsense-mediated mRNA decay, associates with SMG-2 and protein phosphatase 2A. The EMBO journal 121 12554664
1992 Both stimulatory and inhibitory GDP/GTP exchange proteins, smg GDS and rho GDI, are active on multiple small GTP-binding proteins. Biochemical and biophysical research communications 118 1734890
2009 An essential role for the RNA-binding protein Smaug during the Drosophila maternal-to-zygotic transition. Development (Cambridge, England) 117 19234062
2002 Embryonic submandibular gland morphogenesis: stage-specific protein localization of FGFs, BMPs, Pax6 and Pax9 in normal mice and abnormal SMG phenotypes in FgfR2-IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice. Cells, tissues, organs 116 11731698
1989 Purification and characterization from bovine brain cytosol of two GTPase-activating proteins specific for smg p21, a GTP-binding protein having the same effector domain as c-ras p21s. The Journal of biological chemistry 115 2542301
1992 A possible target protein for smg-25A/rab3A small GTP-binding protein. The Journal of biological chemistry 106 1597436
1992 Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes. Molecular and cellular biology 104 1321333
2020 Circular RNA SAMD4A controls adipogenesis in obesity through the miR-138-5p/EZH2 axis. Theranostics 102 32292524
1999 smg-7 is required for mRNA surveillance in Caenorhabditis elegans. Genetics 102 9927455
1990 Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. The Journal of biological chemistry 101 2158984
1989 Phosphorylation of smg p21, a ras p21-like GTP-binding protein, by cyclic AMP-dependent protein kinase in a cell-free system and in response to prostaglandin E1 in intact human platelets. The Journal of biological chemistry 100 2504724
2003 RNA recognition via the SAM domain of Smaug. Molecular cell 98 12820967
2004 SMG-1 is a phosphatidylinositol kinase-related protein kinase required for nonsense-mediated mRNA Decay in Caenorhabditis elegans. Molecular and cellular biology 97 15314158
1991 Molecular cloning of the cDNA for stimulatory GDP/GTP exchange protein for smg p21s (ras p21-like small GTP-binding proteins) and characterization of stimulatory GDP/GTP exchange protein. Molecular and cellular biology 95 1901951
2014 Global regulation of mRNA translation and stability in the early Drosophila embryo by the Smaug RNA-binding protein. Genome biology 94 24393533
1991 Enhancement of the actions of smg p21 GDP/GTP exchange protein by the protein kinase A-catalyzed phosphorylation of smg p21. The Journal of biological chemistry 91 1901063
1991 Role of the C-terminal region of smg p25A in its interaction with membranes and the GDP/GTP exchange protein. Molecular and cellular biology 88 1899908
1989 Tissue distribution of smg p25A, a ras p21-like GTP-binding protein, studied by use of a specific monoclonal antibody. Biochemical and biophysical research communications 83 2504158
1997 smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 82 9275202
1994 The Dbl oncogene product as a GDP/GTP exchange protein for the Rho family: its properties in comparison with those of Smg GDS. Biochemical and biophysical research communications 81 8297393
2005 Mammalian Smaug is a translational repressor that forms cytoplasmic foci similar to stress granules. The Journal of biological chemistry 80 16221671
1992 The geranylgeranyl moiety but not the methyl moiety of the smg-25A/rab3A protein is essential for the interactions with membrane and its inhibitory GDP/GTP exchange protein. The Journal of biological chemistry 80 1315770
2002 AE4 is a DIDS-sensitive Cl(-)/HCO(-)(3) exchanger in the basolateral membrane of the renal CCD and the SMG duct. American journal of physiology. Cell physiology 77 12225984
1988 Phosphorylation by cyclic AMP-dependent protein kinase of a human platelet Mr 22,000 GTP-binding protein (smg p21) having the same putative effector domain as the ras gene products. Biochemical and biophysical research communications 77 2849942
1990 Tissue and subcellular distributions of the smg-21/rap1/Krev-1 proteins which are partly distinct from those of c-ras p21s. Molecular and cellular biology 76 2111441
1989 Tissue-specific expression of a novel GTP-binding protein (smg p25A) mRNA and its increase by nerve growth factor and cyclic AMP in rat pheochromocytoma PC-12 cells. Biochemical and biophysical research communications 76 2537071
2012 SMG-1 and mTORC1 act antagonistically to regulate response to injury and growth in planarians. PLoS genetics 75 22479207
2012 Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. Clinical cancer research : an official journal of the American Association for Cancer Research 73 22247495
2010 Characterization of SMG-9, an essential component of the nonsense-mediated mRNA decay SMG1C complex. Nucleic acids research 73 20817927
2006 Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. Molecular therapy : the journal of the American Society of Gene Therapy 72 16807116
2011 The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes & development 70 21245168
2010 Smaug assembles an ATP-dependent stable complex repressing nanos mRNA translation at multiple levels. The EMBO journal 68 21081899
1992 smg/rap1/Krev-1 p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells. Oncogene 68 1323817
2005 The role of SMG-1 in nonsense-mediated mRNA decay. Biochimica et biophysica acta 67 16289965
1991 A mammalian inhibitory GDP/GTP exchange protein (GDP dissociation inhibitor) for smg p25A is active on the yeast SEC4 protein. Molecular and cellular biology 67 1901952
2013 Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay. Genes to cells : devoted to molecular & cellular mechanisms 60 23356578
2001 Stop making nonSense: the C. elegans smg genes. Trends in genetics : TIG 60 11672865
1996 SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. The Journal of biological chemistry 60 8900189
1992 Neonatal rat submandibular gland protein SMG-A and parotid secretory protein are alternatively regulated members of a salivary protein multigene family. The Journal of biological chemistry 59 1370829
2020 SMAUG: Analyzing single-molecule tracks with nonparametric Bayesian statistics. Methods (San Diego, Calif.) 56 32247784
1991 Role of the C-terminal region of smg p21, a ras p21-like small GTP-binding protein, in membrane and smg p21 GDP/GTP exchange protein interactions. The Journal of biological chemistry 55 1899665
2008 Drosophila maternal Hsp83 mRNA destabilization is directed by multiple SMAUG recognition elements in the open reading frame. Molecular and cellular biology 54 18794360
2008 A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. PloS one 53 18836529
1990 Molecular cloning of smg p21B and identification of smg p21 purified from bovine brain and human platelets as smg p21B. Biochemical and biophysical research communications 52 2105724
2015 A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation. Nucleic acids research 51 26130714
2012 microRNA-independent recruitment of Argonaute 1 to nanos mRNA through the Smaug RNA-binding protein. EMBO reports 51 23184089
1988 Identification of a platelet Mr 22,000 GTP-binding protein as the novel smg-21 gene product having the same putative effector domain as the ras gene products. Biochemical and biophysical research communications 51 3144274
2010 The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation. Biochemical pharmacology 50 20599799
2007 Caenorhabditis elegans SMG-2 selectively marks mRNAs containing premature translation termination codons. Molecular and cellular biology 47 17562857
1993 Comparison of kinetic properties between two mammalian ras p21 GDP/GTP exchange proteins, ras guanine nucleotide-releasing factor and smg GDP dissociation stimulation. The Journal of biological chemistry 46 8244990
2014 Identification and functional characterization of a flax UDP-glycosyltransferase glucosylating secoisolariciresinol (SECO) into secoisolariciresinol monoglucoside (SMG) and diglucoside (SDG). BMC plant biology 45 24678929
1991 Purification and characterization from rat liver cytosol of a GDP dissociation inhibitor (GDI) for liver 24K G, a ras p21-like GTP-binding protein, with properties similar to those of smg p25A GDI. Biochemistry 44 1899198
1992 Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for c-Ki-ras p21 and smg p21. Oncogene 41 1549351
1989 GTPase activating proteins for the smg-21 GTP-binding protein having the same effector domain as the ras proteins in human platelets. Biochemical and biophysical research communications 38 2539152
2009 The telomeric transcriptome and SMG proteins at the crossroads. Cytogenetic and genome research 37 19188687
2008 A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosis. The Journal of biological chemistry 36 18326048
1989 Intrasynaptosomal distribution of the ras, rho and smg-25A GTP-binding proteins in bovine brain. Brain research. Molecular brain research 36 2515409
2007 Distant N- and C-terminal domains are required for intrinsic kinase activity of SMG-1, a critical component of nonsense-mediated mRNA decay. The Journal of biological chemistry 35 17229728
1991 Inhibition of the action of the stimulatory GDP/GTP exchange protein for smg p21 by the geranylgeranylated synthetic peptides designed from its C-terminal region. The Journal of biological chemistry 34 1939117
2013 SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways. Cell cycle (Georgetown, Tex.) 30 24107632
2017 SMG-1 inhibition by miR-192/-215 causes epithelial-mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling. Cancer medicine 29 29239144
1993 A Drosophila homolog of bovine smg p25a GDP dissociation inhibitor undergoes a shift in isoelectric point in the developmental mutant quartet. Molecular and cellular biology 29 8417327
1992 Phosphorylation of smg p21B/rap1B p21 by cyclic GMP-dependent protein kinase. FEBS letters 29 1551424
1991 Stoichiometric interaction of smg p21 with its GDP/GTP exchange protein and its novel action to regulate the translocation of smg p21 between membrane and cytoplasm. Biochemical and biophysical research communications 29 1900001
1989 Kinetic analysis of the binding of guanine nucleotide to bovine brain smg p25A. Biochemical and biophysical research communications 28 2502110
2013 Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America 27 23983263
1992 Localization of smg p25A/rab3A p25, a small GTP-binding protein, at the active zone of the rat neuromuscular junction. Biochemical and biophysical research communications 27 1324664
2016 A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type. Oncology letters 26 26998062
2013 Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. PLoS genetics 25 23637619
1989 Identification of a major GTP-binding protein in bovine aortic smooth muscle membranes as smg p21, a GTP-binding protein having the same effector domain as ras p21s. Biochemical and biophysical research communications 25 2551287
2021 RNA-binding protein SAMD4A inhibits breast tumor angiogenesis by modulating the balance of angiogenesis program. Cancer science 24 34219323
2015 Stem Cell-Soluble Signals Enhance Multilumen Formation in SMG Cell Clusters. Journal of dental research 24 26285810
2009 Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. The Journal of biological chemistry 24 19406746
2001 Molecular identification of smg-4, required for mRNA surveillance in C. elegans. Gene 24 11368911
2023 RNA binding proteins Smaug and Cup induce CCR4-NOT-dependent deadenylation of the nanos mRNA in a reconstituted system. Nucleic acids research 23 36951092
2000 Characterization of the calcium signaling system in the submandibular cell line SMG-C6. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 21 11082216
2014 Expression and significance of the novel tumor-suppressor gene SMG-1 in hepatocellular carcinoma. Oncology reports 19 24700316