Affinage

TRAM2

Translocating chain-associated membrane protein 2 · UniProt Q15035

Length
370 aa
Mass
43.3 kDa
Annotated
2026-06-10
27 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAM2 is a translocon-associated endoplasmic reticulum membrane protein that couples local Ca2+ provision to collagen biosynthesis and governs the topology of select substrate proteins during their cotranslational insertion into the ER. Through its C-terminal domain, TRAM2 binds and modulates the ER Ca2+ pump SERCA2b to locally enrich Ca2+ at the site of collagen synthesis, a function required for proper triple-helical folding of type I collagen; loss of the C-terminus or pharmacological SERCA inhibition with thapsigargin blocks collagen folding and increases its intracellular degradation (PMID:14749390), and in osteoblasts this SERCA2b coupling links Ca2+ to collagen production and biomineralization (PMID:34047068). In parallel, TRAM2 acts as a ceramide-binding protein that mediates regulated alternative translocation (RAT): it normally promotes ER-luminal translocation of the first transmembrane helix of TM4SF20, whereas ceramide binding releases this requirement and inverts TM4SF20 topology to activate CREB3L1 cleavage (PMID:27499293, PMID:34793833). Transcriptionally, TRAM2 lies downstream of BMP/Runx2 signaling in osteoblasts, where Runx2 directly occupies the Tram2 locus and BMP-2 relieves its repression (PMID:17486635), and downstream of a YAP/TEAD4 enhancer axis in cancer, where it supports proliferation, migration, and invasion in part through the secreted client FSTL-1 (PMID:33514403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    Established the founding mechanistic role of TRAM2 by showing it physically couples the ER Ca2+ pump to collagen biosynthesis, explaining how an ER membrane protein enables proper triple-helical collagen folding.

    Evidence Yeast two-hybrid, co-immunoprecipitation, C-terminal deletion mutagenesis, and thapsigargin inhibition in a hepatic stellate cell activation model

    PMID:14749390

    Open questions at the time
    • Direct measurement of local Ca2+ elevation at the translocon not shown
    • Whether collagen contacts TRAM2 directly versus via SERCA2b/Ca2+ not resolved
    • Structural basis of the C-terminal SERCA2b interaction unknown
  2. 2007 Medium

    Placed TRAM2 transcriptionally within osteoblast differentiation by identifying it as a direct Runx2 target relieved by BMP-2, connecting its collagen-supporting function to a known bone master-regulator pathway.

    Evidence ChIP Display, Runx2 overexpression, and BMP-2 treatment with mRNA analysis across multiple cell lines

    PMID:17486635

    Open questions at the time
    • Functional consequence of Runx2 occupancy on bone phenotype not tested
    • Direct regulatory element within the locus not finely mapped
    • Single lab
  3. 2016 High

    Revealed a second, topology-determining function: TRAM2 is required for ER-luminal translocation of a substrate transmembrane helix and is bypassed by ceramide to drive regulated alternative translocation and CREB3L1 activation.

    Evidence Knockdown/overexpression with topology assays and CREB3L1 cleavage readout under ceramide treatment

    PMID:27499293

    Open questions at the time
    • How ceramide alters TRAM2-substrate engagement mechanistically not defined
    • Breadth of substrates beyond TM4SF20 unknown
    • Link between RAT function and collagen/SERCA2b function unexplored
  4. 2021 High

    Defined the molecular basis of ceramide regulation by demonstrating TRAM2 directly binds ceramide, with binding correlating to its ability to trigger RAT.

    Evidence Photoactivatable clickable ceramide analog crosslinking, click-chemistry pulldown, long-chain ceramide competition, and functional RAT assay

    PMID:34793833

    Open questions at the time
    • Ceramide-binding site on TRAM2 not mapped
    • Stoichiometry and structural change upon binding unknown
    • Whether ceramide binding affects the SERCA2b/collagen function not tested
  5. 2021 Medium

    Extended the SERCA2b coupling model to bone by showing TRAM2 modulates SERCA2b activity to link Ca2+ enrichment with collagen production and mineralization.

    Evidence Co-immunoprecipitation, TRAM2 silencing, and biomineralization assays in osteoblasts

    PMID:34047068

    Open questions at the time
    • Quantitative effect on SERCA2b pump kinetics not measured
    • Single lab
    • In vivo bone phenotype not established
  6. 2021 Medium

    Connected TRAM2 to oncogenic transcriptional control by identifying it as a YAP/TEAD4 enhancer target whose loss phenocopies YAP loss and whose function involves the secreted client FSTL-1.

    Evidence Genome-wide YAP/TEAD4 ChIP, CRISPR enhancer deletion with proliferation/migration/invasion assays, and FSTL-1 client identification

    PMID:33514403

    Open questions at the time
    • Mechanism by which TRAM2 handles FSTL-1 as a client not defined
    • Whether collagen/Ca2+ function underlies the oncogenic phenotype unclear
    • Single lab
  7. 2021 Medium

    Implicated TRAM2-SERCA function in host support of intracellular bacterial infection, broadening the physiological relevance of the SERCA interaction.

    Evidence Genome-wide shRNA screen with silencing validation and thapsigargin treatment measuring intracellular MRSA load

    PMID:31659191

    Open questions at the time
    • Direct molecular link between TRAM2-SERCA Ca2+ and bacterial survival not dissected
    • Whether collagen pathway is involved unknown
    • Single lab
  8. 2022 Medium

    Added post-transcriptional control by establishing a YY1-RBM15B axis that stabilizes TRAM2 mRNA via m6A modification in hepatocellular carcinoma.

    Evidence m6A assays, RBM15B overexpression/knockdown, mRNA stability assays, and luciferase/ChIP for YY1 binding

    PMID:35494016

    Open questions at the time
    • Specific m6A sites on TRAM2 transcript not mapped
    • Downstream functional output of stabilized TRAM2 not detailed
    • Single lab
  9. 2021 Low

    Associated TRAM2 with additional cancer and ECM-regulatory contexts, suggesting broader roles in collagen/ECM output and tumor signaling.

    Evidence miRNA mimic/inhibitor and corneal model (miR-432-5p); siRNA with PI3K activator rescue and xenograft (glioma)

    PMID:34826698 PMID:34923312

    Open questions at the time
    • Direct miRNA-target repression not confirmed by luciferase in the corneal study
    • PI3K/AKT/mTOR placement rests on single pharmacological rescue
    • Mechanistic link to core TRAM2 ER functions not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRAM2's two molecular functions — SERCA2b/Ca2+-coupled collagen folding and ceramide-gated substrate translocation — are integrated within a single translocon-associated protein, and whether they share structural determinants, remains unresolved.
  • No structural model of TRAM2
  • Ceramide-binding and SERCA2b-binding interfaces not jointly mapped
  • Unclear whether oncogenic phenotypes derive from collagen function, RAT function, or both

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1474244 Extracellular matrix organization 2 R-HSA-392499 Metabolism of proteins 2
Partners
ATP2A2COL1A1FSTL1TM4SF20

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TRAM2 protein interacts with the ER Ca2+ pump SERCA2b via its C-terminal domain, as demonstrated by yeast two-hybrid screen and co-immunoprecipitation in human cells. Deletion of the C-terminal part of TRAM2 inhibits type I collagen synthesis during hepatic stellate cell activation. TRAM2 also co-precipitates with anti-collagen antibody, suggesting direct interaction. The pharmacological SERCA2b inhibitor thapsigargin phenocopies TRAM2 C-terminal deletion, inhibiting triple-helical collagen folding and increasing intracellular degradation. Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, pharmacological inhibition (thapsigargin), hepatic stellate cell activation model Molecular and cellular biology High 14749390
2016 TRAM2 is required for translocation of the N-terminus of the first transmembrane helix of TM4SF20 into the ER lumen. In the absence of ceramide, TRAM2 facilitates this translocation; in the presence of ceramide, TM4SF20 translocation becomes TRAM2-independent and its membrane topology is inverted (regulated alternative translocation, RAT), leading to stimulation of CREB3L1 cleavage. Genetic knockdown/overexpression, topology assays, ceramide treatment, functional readout of CREB3L1 proteolytic processing Molecular cell High 27499293
2021 TRAM2 directly interacts with ceramide: using a photoactivatable and clickable short-chain ceramide analog (pac-C7-Cer), TRAM2 (and its homolog TRAM1) were identified as ceramide-binding proteins. This binding was competed by naturally occurring long-chain ceramides, and ceramide binding to TRAM2 correlated with the ability to induce regulated alternative translocation (RAT) of TM4SF20. Photoactivatable ceramide analog (pac-C7-Cer) crosslinking, click chemistry pulldown, competition assay with long-chain ceramides, functional RAT assay The Journal of biological chemistry High 34793833
2021 TRAM2 directly interacts with SERCA2b and modulates SERCA2b activity to couple calcium enrichment with collagen biosynthesis in osteoblasts. Silencing TRAM2 disrupts the relationship between calcium concentration and collagen production, causing poor mineralization. Co-immunoprecipitation, TRAM2 silencing (siRNA/shRNA), biomineralization assay in osteoblasts Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34047068
2007 Tram2 is a direct transcriptional target of the osteoblast master regulator Runx2, identified by ChIP Display in MC3T3-E1 osteoblastic cells. Runx2 occupies a genomic region within the Tram2 locus. BMP-2 treatment relieves Runx2-mediated suppression of Tram2 in non-osteoblasts and coincides with increased Tram2 mRNA in multiple cell lines, placing Tram2 downstream of BMP/Runx2 signaling in osteoblast function. Chromatin immunoprecipitation (ChIP Display), mRNA expression analysis, BMP-2 treatment, Runx2 overexpression in multiple cell lines Journal of cellular biochemistry Medium 17486635
2018 Knockdown of TRAM2 in oral squamous cell carcinoma (OSCC) cells inhibits cell migration, invasiveness, and transendothelial migration, accompanied by significant decreases in PERK and matrix metalloproteinases MT1-MMP, MMP2, and MMP9, placing TRAM2 upstream of PERK and MMP activation in OSCC metastatic behavior. siRNA knockdown, migration/invasion/transendothelial migration assays, Western blotting for PERK and MMPs Journal of Cancer Medium 30271493
2021 TRAM2 is a transcriptional target of the YAP/TEAD4 enhancer axis. Genetic deletion of EnhancerTRAM2 reduces TRAM2 expression and phenocopies YAP loss-of-function in proliferation, migration, and invasion. FSTL-1 is identified as a major direct client (secreted factor) of TRAM2 involved in these oncogenic phenotypes. Genome-wide ChIP profiling (YAP/TEAD4), CRISPR-mediated enhancer deletion, proliferation/migration/invasion assays, identification of FSTL-1 as TRAM2 client Genome biology Medium 33514403
2021 TRAM2 silencing significantly reduces intracellular bacterial load of Staphylococcus aureus while restoring host cell viability. Treatment with the SERCA inhibitor thapsigargin (which targets the TRAM2-SERCA interaction) also halted intracellular MRSA survival, indicating TRAM2's role in supporting intracellular bacterial infection via its interaction with SERCA pumps. shRNA screen (genome-wide), TRAM2 silencing validation, thapsigargin treatment, intracellular bacterial load quantification Scientific reports Medium 31659191
2022 RBM15B, transcriptionally activated by YY1, regulates TRAM2 mRNA stability in an m6A-dependent manner in hepatocellular carcinoma cells, establishing a YY1-RBM15B-TRAM2 regulatory axis. m6A modification assay, RBM15B overexpression/knockdown, mRNA stability assay, luciferase and ChIP assays for YY1 binding Frontiers in oncology Medium 35494016
2021 miR-432-5p, secreted in exosomes from iPSC-MSCs, suppresses TRAM2 expression in corneal stromal stem cells, reducing collagen biosynthesis and ECM deposition (downregulating COL1A1, COL5A1, COL5A2 mRNA), and promoting corneal stroma regeneration. miRNA mimic/inhibitor transfection, luciferase reporter assay (implied by direct repression claim), mRNA expression analysis, in vivo corneal model Biomaterials Low 34923312
2021 TRAM2 knockdown suppresses glioma cell proliferation, invasion, migration, and EMT in vitro and inhibits tumorigenicity in vivo. TRAM2 is positively associated with PI3K/AKT/mTOR signaling activation, and the PI3K activator 740Y-P reverses the effects of TRAM2 silencing, placing TRAM2 upstream of PI3K/AKT/mTOR in glioma. siRNA knockdown, PI3K pathway inhibition/activation (740Y-P), proliferation/invasion/migration assays, xenograft model Biochemical and biophysical research communications Low 34826698

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration. Biomaterials 200 34923312
2003 Identification of a novel adrenomedullin gene family in teleost fish. Biochemical and biophysical research communications 71 14623291
2004 TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis. Molecular and cellular biology 67 14749390
2016 Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Molecular cell 37 27499293
2014 Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics. Molecular endocrinology (Baltimore, Md.) 37 25148458
2008 Preimplantation genetic diagnosis for autosomal recessive polycystic kidney disease. Reproductive biomedicine online 31 18252063
2022 YY1-Targeted RBM15B Promotes Hepatocellular Carcinoma Cell Proliferation and Sorafenib Resistance by Promoting TRAM2 Expression in an m6A-Dependent Manner. Frontiers in oncology 27 35494016
2021 Calcium-Collagen Coupling is Vital for Biomineralization Schedule. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 34047068
2018 Overexpression of Translocation Associated Membrane Protein 2 Leading to Cancer-Associated Matrix Metalloproteinase Activation as a Putative Metastatic Factor for Human Oral Cancer. Journal of Cancer 22 30271493
2021 A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis. Genome biology 20 33514403
2018 Genome-wide scan for commons SNPs affecting bovine leukemia virus infection level in dairy cattle. BMC genomics 20 29439661
2007 Identification of novel Runx2 targets in osteoblasts: cell type-specific BMP-dependent regulation of Tram2. Journal of cellular biochemistry 18 17486635
2008 Three de novo losses and one insertion within a pericentric inversion of chromosome 6 in a patient with complete absence of expressive speech and reduced pain perception. European journal of medical genetics 17 19041736
2021 TRAM2 promotes the malignant progression of glioma through PI3K/AKT/mTOR pathway. Biochemical and biophysical research communications 16 34826698
2020 Anti-cyclic citrullinated peptide antibodies are associated with radiographic damage but not disease activity in early rheumatoid arthritis diagnosed in 2006-2011. Scandinavian journal of rheumatology 16 32856532
2006 Dual control of quorum sensing by two TraM-type antiactivators in Agrobacterium tumefaciens octopine strain A6. Journal of bacteriology 13 16547030
2023 Downregulation of circ-STK39 suppresses pancreatic cancer progression by sponging mir-140-3p and regulating TRAM2-mediated epithelial-mesenchymal transition. Apoptosis : an international journal on programmed cell death 12 37041422
2019 Identification of novel targets for host-directed therapeutics against intracellular Staphylococcus aureus. Scientific reports 12 31659191
2006 Crystal structure and mechanism of TraM2, a second quorum-sensing antiactivator of Agrobacterium tumefaciens strain A6. Journal of bacteriology 12 16997969
2006 Mutation analyses of genes on 6p12-p11 in patients with juvenile myoclonic epilepsy. Neuroscience letters 11 16876319
2021 Identification of TRAMs as sphingolipid-binding proteins using a photoactivatable and clickable short-chain ceramide analog. The Journal of biological chemistry 10 34793833
2021 A comparative study of libido in drakes: from phenotypes to molecules. Poultry science 9 34700098
2002 Identification and mutational analysis of candidate genes for juvenile myoclonic epilepsy on 6p11-p12: LRRC1, GCLC, KIAA0057 and CLIC5. Epilepsy research 9 12200217
2014 Identification and characterization of a second quorum-sensing system in Agrobacterium tumefaciens A6. Journal of bacteriology 8 24464459
2020 Genes regulating membrane-associated E-cadherin and proliferation in adenomatous polyposis coli mutant colon cancer cells: High content siRNA screen. PloS one 5 33057364
2021 Identification of Four Enhancer-Associated Genes as Risk Signature for Diffuse Glioma Patients. Journal of molecular neuroscience : MN 3 34462884
2026 Molecular Subtype Classification and Mechanistic Investigation Based on Ferroptosis-Related lncRNAs in Ovarian Cancer. Genetics research 0 41858239

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