TMSB10

TMSB10 (thymosin β10) is a G-actin-binding protein that governs actin dynamics to drive cell proliferation, migration, and invasion across multiple cancers (PMID:39368341, PMID:32319572). Mechanistically, TMSB10 binds G-actin and disrupts the equilibrium between G-actin-TMSB10 and G-actin-ATP interactions, controlling F-actin formation required for cell migration; its degradation via the autophagy-lysosome pathway suppresses NSCLC proliferation, migration, and invasion (PMID:39368341). In clear cell renal cell carcinoma, TMSB10 acts upstream of a PI3K/VEGF signaling axis, with knockdown reducing PI3K phosphorylation and VEGF expression (PMID:32319572). TMSB10 expression is controlled both transcriptionally, through JUN binding to its promoter (PMID:35414502), and epigenetically, through DNMT1-maintained methylation of the miR-152-3p promoter that otherwise targets and suppresses TMSB10 (PMID:32918845). Beyond cancer, TMSB10 is a positive regulator of TGF-β/SMAD signaling, promoting SMAD2/3 phosphorylation and ECM accumulation in renal fibroblasts (PMID:41497884), and in fetal testis it transiently marks Leydig cell progenitors where it suppresses RAS/ERK signaling to drive fetal Leydig cell differentiation (PMID:36109592).

1. 2020 Low

   Established that TMSB10 functions upstream of an oncogenic signaling axis, addressing how its expression translates into tumor cell behavior.

   Evidence TMSB10 knockdown in ccRCC cell lines with proliferation/migration/invasion assays and western blotting for PI3K phosphorylation and VEGF

   PMID:32319572

   Open questions at the time

   • Single knockdown approach without reconstitution or epistasis confirmation
   • Does not establish whether PI3K/VEGF effects are direct or downstream of actin changes
   • No mechanism linking TMSB10 to PI3K activation
2. 2020 Medium

   Identified an epigenetic control circuit explaining how TMSB10 is maintained at high levels in cancer, via DNMT1/miR-152-3p.

   Evidence Methylation detection, DNMT1/miR-152-3p transfection and targeting analysis in CRC cells with in vivo tumor growth assays

   PMID:32918845

   Open questions at the time

   • Direct binding of miR-152-3p to the TMSB10 transcript inferred from targeting analysis
   • Does not address whether this circuit operates outside colorectal cancer
3. 2022 Medium

   Defined a developmental role distinct from cancer, showing TMSB10 drives fetal Leydig cell differentiation by suppressing RAS/ERK.

   Evidence scRNA-seq identification plus functional manipulation in mouse fetal testis with RAS/ERK and PI3K/AKT pathway analysis

   PMID:36109592

   Open questions at the time

   • Molecular mechanism by which TMSB10 suppresses RAS/ERK not resolved
   • Relationship between actin-binding activity and ERK suppression unclear
4. 2022 Medium

   Identified JUN as a direct transcriptional activator of TMSB10, providing an upstream determinant of its oncogenic expression.

   Evidence ChIP confirmation of JUN binding to the TMSB10 promoter with qRT-PCR and proliferation/apoptosis assays in ccRCC cells

   PMID:35414502

   Open questions at the time

   • Does not establish whether JUN regulation interacts with the DNMT1/miR-152-3p axis
   • Single lab, single tumor type
5. 2024 Medium

   Resolved the core actin-related mechanism, showing TMSB10 binds G-actin and that its autophagic degradation disrupts F-actin formation for migration.

   Evidence GST pull-down, confocal imaging, western blotting, and TMSB10 KD/OE with proliferation/transwell assays in NSCLC; Urolithin A as a degradation inducer

   PMID:39368341

   Open questions at the time

   • Structural basis of G-actin-TMSB10 binding not determined
   • Autophagy-lysosome degradation mechanism characterized only via Urolithin A treatment
6. 2024 Low

   Showed the TMSB10 UTR confers high mRNA expression in antigen-presenting cells, a property exploitable for mRNA vaccine design.

   Evidence GEO mining, reporter assays in APCs/293T, and in vivo mRNA vaccine immune readouts

   PMID:38675814

   Open questions at the time

   • Mechanism of high TMSB10 mRNA abundance in dendritic cells not dissected
   • Concerns the UTR element rather than TMSB10 protein function
7. 2025 Medium

   Extended TMSB10 function beyond cancer to fibrosis, positioning it as a positive regulator of TGF-β/SMAD2/3 signaling.

   Evidence Tmsb10 knockdown in NIH-3T3 fibroblasts and a diabetic mouse model with fibrosis marker and SMAD2/3 phosphorylation readouts; scRNA-seq for identification

   PMID:41497884

   Open questions at the time

   • Mechanism linking TMSB10 to SMAD2/3 phosphorylation not defined
   • Single lab; relationship to actin-binding activity unaddressed
8. 2025 Low

   Linked TMSB10 to immune microenvironment remodeling, showing it skews macrophages toward an M2 phenotype in prostate cancer.

   Evidence siRNA knockdown and overexpression in prostate cancer cell lines with co-culture macrophage polarization and cytokine assays

   PMID:40307738

   Open questions at the time

   • No molecular mechanism identified for macrophage polarization
   • Co-culture readout without in vivo immune validation

• How TMSB10's single G-actin-binding activity mechanistically converges on the diverse signaling outputs (PI3K/VEGF, RAS/ERK, TGF-β/SMAD) attributed to it remains unresolved.
• No unifying mechanism connecting actin sequestration to specific signaling cascades
• No structural model of TMSB10 in complex with partners
• Tissue-specific determinants of opposing roles (differentiation vs. proliferation) unknown