Affinage

SAMD4B

Protein Smaug homolog 2 · UniProt Q5PRF9

Round 2 corrected
Length
694 aa
Mass
75.5 kDa
Annotated
2026-04-28
40 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SAMD4B (Smaug homolog 2) is a SAM-domain-containing RNA-binding protein that functions as a translational and transcriptional repressor and a nutrient-sensitive regulator of Wnt/β-catenin signaling. Its SAM domain mediates transcriptional suppression of AP-1, p53, and p21 reporter activities (PMID:20510020), while SAMD4B also stabilizes β-catenin mRNA to activate TCF/LEF-dependent transcription of Wnt target genes including Cyclin D1, c-Myc, and Axin2 (PMID:41154652). In arginine-replete conditions, BAG2 directly binds and sequesters SAMD4B, preventing β-catenin degradation; upon arginine deprivation, BAG2 releases SAMD4B, leading to β-catenin degradation and ATF4 stabilization that promotes cell survival under nutritional stress (PMID:40555234). SAMD4B mRNA is itself a validated direct target of miR-451, linking its expression to post-transcriptional control in colorectal cancer (PMID:34109425).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2010 Medium

    The question of what molecular activity SAMD4B possesses was addressed by showing that its SAM domain is necessary and sufficient for transcriptional suppression of AP-1, p53, and p21 reporters, establishing SAMD4B as a SAM-domain-dependent transcriptional repressor.

    Evidence Luciferase reporter assays with deletion mutants and siRNA rescue in mammalian cells

    PMID:20510020

    Open questions at the time
    • No endogenous target genes validated; all assays used exogenous reporters
    • Mechanism of SAM-domain-mediated repression (direct DNA binding vs. protein–protein interaction) not determined
    • Single lab, not independently replicated
  2. 2021 Medium

    The upstream regulation of SAMD4B expression was clarified by demonstrating that miR-451 directly targets the SAMD4B 3′-UTR, and that SAMD4B overexpression rescues miR-451-induced growth suppression, establishing SAMD4B as a functionally relevant miR-451 effector in colorectal cancer.

    Evidence Dual-luciferase 3′-UTR reporter assay, rescue experiments with proliferation/migration/apoptosis readouts, nude mouse xenografts

    PMID:34109425

    Open questions at the time
    • Endogenous SAMD4B protein reduction by miR-451 not quantified at protein level across multiple cell lines
    • Downstream mechanism by which SAMD4B promotes proliferation was not identified
    • Single lab study
  3. 2025 Medium

    A key mechanistic question—how SAMD4B connects to a major signaling pathway—was resolved by showing that SAMD4B stabilizes β-catenin mRNA, elevates β-catenin protein, and activates TCF/LEF transcription of Wnt target genes, with pharmacological Wnt inhibition (XAV-939) abolishing SAMD4B's pro-oncogenic effects.

    Evidence Overexpression/knockdown functional assays, qRT-PCR, western blotting, and XAV-939 inhibitor treatment in breast cancer cells

    PMID:41154652

    Open questions at the time
    • Direct RNA-binding biochemistry (e.g., CLIP, EMSA) for β-catenin mRNA not shown
    • Contribution of the SAM domain to mRNA stabilization not tested
    • Single lab, no in vivo validation
  4. 2025 High

    The nutrient-sensing context for SAMD4B function was established: BAG2 directly binds SAMD4B in an arginine-dependent manner, sequestering it under arginine-replete conditions to protect β-catenin, while releasing it upon arginine deprivation to allow β-catenin degradation and ATF4 stabilization—positioning SAMD4B as a regulated switch in nutrient-responsive Wnt signaling.

    Evidence Co-immunoprecipitation, direct binding assays, BAG2-Q167 mutagenesis, arginine-deficiency models, western blotting for β-catenin and ATF4

    PMID:40555234

    Open questions at the time
    • Structural basis of BAG2–SAMD4B interaction unknown
    • Whether SAMD4B degrades β-catenin directly or recruits a destruction complex component is unresolved
    • In vivo physiological relevance in organismal arginine sensing not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether SAMD4B's transcriptional repressor function (via SAM domain) and its mRNA-stabilization activity (on β-catenin mRNA) represent distinct or coupled mechanisms, and no direct RNA-binding targets have been mapped transcriptome-wide.
  • No CLIP-seq or equivalent transcriptome-wide binding map exists
  • Relationship between SAM-domain transcriptional repression and RNA-level regulation is uncharacterized
  • No structural information for SAMD4B or its complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140110 transcription regulator activity 1
Pathway
R-HSA-162582 Signal Transduction 2
Partners
BAG2CTNNB1

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 SAMD4B encodes a 694-amino-acid protein containing a SAM (sterile alpha motif) domain. Overexpression of SAMD4B in mammalian cells inhibits the transcriptional activities of AP-1, p53, and p21, and this inhibitory effect can be relieved by siRNA knockdown. Deletion analysis demonstrated that the SAM domain is the primary region responsible for transcriptional suppression. Transcriptional activity luciferase assays, siRNA knockdown, deletion mutagenesis, Northern blot, RT-PCR BMB reports Medium 20510020
2021 SAMD4B is a direct target of miR-451 in colorectal cancer cells; miR-451 binds the 3'-UTR of SAMD4B mRNA (validated by dual luciferase reporter assay), and overexpression of SAMD4B rescues the anti-proliferative and pro-apoptotic effects of miR-451 overexpression, placing SAMD4B downstream of miR-451 in a pathway promoting CRC cell proliferation and migration. Dual luciferase reporter assay, miRNA target prediction, CCK-8 proliferation assay, Transwell migration assay, flow cytometry, western blotting, nude mouse xenograft Molecular medicine reports Medium 34109425
2024 SAMD4B mediates 2'-O-methylation modification of APOA2 mRNA at its C-terminus, leading to instability of APOA2 mRNA. Decreased APOA2 in turn attenuates PD-L1 protein levels through direct interaction, thereby modulating the tumor immune microenvironment. SAMD4B expression is increased by reduced mutations in upstream NOTCH1 and NOTCH2. 2'-O-methylation modification assay, multiplex immunofluorescence staining, single-cell RNA sequencing in PDX mouse models Cell death & disease Low 38886351
2025 BAG2 directly binds SAMD4B; when arginine is abundant, BAG2-SAMD4B interaction is strengthened, preventing β-catenin degradation and activating the Wnt/β-catenin pathway for cell growth. Upon arginine deficiency, BAG2 (which directly senses arginine via its Q167 residue) releases SAMD4B, leading to β-catenin degradation and stabilization of ATF4 protein to promote cell survival under nutritional stress. Thus SAMD4B functions as a regulated effector in a BAG2-arginine sensing axis controlling β-catenin stability. Unbiased screening, Co-immunoprecipitation, direct binding assays, arginine-deficiency cell models, mutagenesis (Q167), western blotting for β-catenin and ATF4 Molecular cell High 40555234
2025 SAMD4B promotes breast cancer cell proliferation, migration, invasion, and EMT, and accelerates G1-to-S phase cell cycle progression by modulating p53 expression. Mechanistically, SAMD4B stabilizes β-catenin mRNA, increasing β-catenin protein levels and enhancing TCF/LEF transcriptional activity along with upregulation of Wnt target genes Cyclin D1, c-Myc, and Axin2. Pharmacological inhibition of Wnt/β-catenin signaling with XAV-939 abrogates SAMD4B's pro-oncogenic effects. SAMD4B overexpression and knockdown functional assays, cell proliferation, migration and invasion assays, cell cycle analysis, western blotting, qRT-PCR, XAV-939 inhibitor treatment Biomolecules Medium 41154652

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PloS one 312 23251661
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2004 Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins. The Journal of biological chemistry 185 15161933
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2013 The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells. PloS one 85 23667531
2005 Mammalian Smaug is a translational repressor that forms cytoplasmic foci similar to stress granules. The Journal of biological chemistry 80 16221671
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2011 Systematic nomenclature for the PLUNC/PSP/BSP30/SMGB proteins as a subfamily of the BPI fold-containing superfamily. Biochemical Society transactions 56 21787333
2003 Psp and Smgb: a model for developmental and functional regulation in the rat major salivary glands. Biochemical Society transactions 24 12887304
2010 SAMD4B, a novel SAM-containing protein, inhibits AP-1-, p53- and p21-mediated transcriptional activity. BMB reports 16 20510020
2000 Structure and chromosomal localization of the rat salivary Psp and Smgb genes. Gene 14 10675608
2000 Submandibular gland adenocarcinoma of intercalated duct origin in Smgb-Tag mice. Laboratory investigation; a journal of technical methods and pathology 12 11092526
2021 miR‑451 suppresses the malignant characteristics of colorectal cancer via targeting SAMD4B. Molecular medicine reports 11 34109425
2005 Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model. Laboratory investigation; a journal of technical methods and pathology 10 15880136
2025 BAG2 releases SAMD4B upon sensing of arginine deficiency to promote tumor cell survival. Molecular cell 8 40555234
2024 Synergistic immunochemotherapy targeted SAMD4B-APOA2-PD-L1 axis potentiates antitumor immunity in hepatocellular carcinoma. Cell death & disease 7 38886351
2025 Oncogenic Role of SAMD4B in Breast Cancer Progression by Activating Wnt/β-Catenin Pathway. Biomolecules 0 41154652