TGF-β/Smad signaling pathway

TGF-β family ligands signal through type II/type I serine-threonine kinase receptors to activate receptor-regulated SMADs (e.g., SMAD2/3), which partner with SMAD4 for nuclear transcriptional control. The pathway is central to development, immune homeostasis, fibrosis, and context-dependent tumor suppression versus pro-metastatic programs.

1. Key targets

Core nodes

  • TGFBR1 / ALK5 & TGFBR2

    Type I/II receptor kinases; ligand-induced assembly and trans-phosphorylation initiate SMAD cascades.

  • SMAD2 / SMAD3

    R-SMADs; C-terminal SSXS phosphorylation, then complex formation with SMAD4.

  • SMAD4

    Co-SMAD; SMAD4 loss (e.g., pancreatic cancer) reframes downstream TGF-β biology.

Upstream & cofactors

  • TGFB1/2/3; BMP / Activin / GDF parallel branches
  • Co-receptors such as TGFBR3 and Endoglin (ENG)
  • SMAD7 / SMURF1/2 feedback and receptor turnover

Downstream & non-canonical

  • SNAIL/SLUG, ID family, cell-cycle and matrix programs
  • TAK1–JNK/p38, PI3K, Rho-like GTPases (context-dependent)

Supplement: TGF-β/Smad–related targets (gene symbols)

Below the overview, HGNC symbols group TGF-β superfamily ligands (including latent complexes), BMP/GDF/activin/nodal arms, extracellular antagonists, type I–III receptors & membrane helpers, R-/co-/I-SMADs with ubiquitin/DUB regulators, nuclear cofactors, EMT/matrix readouts, non-canonical TAK1–MAPK nodes, and PI3K–mTOR crosstalk. SMAD9 is the principal BMP-branch R-SMAD (historically SMAD8/BMP-SMAD). Annotate splice isoforms and context-dependent coupling with databases/papers.

TGF-β ligands & latent complex

TGF-β ligands & latent TGF-β–binding proteins

TGFB1, TGFB2, TGFB3, TGFB1I1, LTBP1, LTBP2, LTBP3, LTBP4, FBN1, FBN2, FBN3, LRRC32, ITGB6, ITGB8, ITGAV

BMP / GDF / activin / nodal arms

BMP / GDF family ligands

BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP9, BMP10, BMP15, GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, GDF15

Activin / inhibin / Nodal / Lefty / AMH

INHA, INHBA, INHBB, INHBC, INHBE, NODAL, LEFTY1, LEFTY2, AMH, FST, FSTL1, FSTL3, FSTL4, FSTL5

Extracellular modulation & processing

Extracellular antagonists & modulators

NOG, CHRD, CHRDL1, CHRDL2, GREM1, GREM2, DAND5, CER1, USAG1, SOST, BAMBI, CRIM1, CRIM2, ECM1, THBS1, THBS2, THBS3, THBS4

Proprotein convertases (ligand maturation)

FURIN, PCSK5, PCSK6, PCSK7, PACE4, TMPRSS6

Receptors & membrane helpers

Type II receptors & type III co-receptors

TGFBR2, ACVR2A, ACVR2B, BMPR2, AMHR2, TGFBR3, ENG, RGMA, RGMB, NEO1, HJV, SCUBE1, SCUBE2, SCUBE3, DCN, BGN, LUM

Type I receptor kinases (ALK family)

TGFBR1 is ALK5; BMPR1A/1B are often called ALK3/6; ACVRL1 is ALK1.

TGFBR1, ACVR1, ACVR1B, ACVR1C, BMPR1A, BMPR1B, ACVRL1

SMAD core & regulation

R-SMADs, co-SMAD & inhibitory SMADs

SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, SMAD7, SMAD9

SMAD anchoring, ubiquitination & deubiquitin regulators

ZFYVE9, STRAP, SMURF1, SMURF2, TRIM33, NEDD4L, WWP1, UBE2D1, UBE2D3, USP9X, USP11, USP15, USP33, USP34, STUB1, RNF111, PPM1A, PPP2CA, PPP2CB

Nuclear cofactors & transcriptional adaptors (selected)

FOXH1, SKI, SKIL, TGIF1, TGIF2, TGIF2LX, TGIF2LY, MEN1, CTNNBIP1, RUNX1, RUNX2, RUNX3, EP300, CREBBP, MED1, MED15, MED24, MED31

EMT & matrix readouts

EMT transcription factors & matrix readout genes

SNAI1, SNAI2, TWIST1, TWIST2, ZEB1, ZEB2, ID1, ID2, ID3, ID4, CDH1, CDH2, VIM, COL1A1, COL1A2, COL3A1, ACTA2, TAGLN, FN1

Non-canonical MAPK & mTOR crosstalk

Non-canonical: TAK1–TAB–TRAF & MAPK branches

MAP3K7, TAB1, TAB2, TAB3, TRAF4, TRAF6, TRAF2, MAPK8, MAPK9, MAPK10, MAPK14, MAPK11, MAPK12, MAPK13, MAPKAPK2, MAPKAPK3, RHOA, RHOC, CDC42, RAC1, ROCK1, ROCK2, PAK1, PAK2

Crosstalk with PI3K–Akt / mTOR (selected)

PIK3CA, PIK3CB, PIK3CD, AKT1, AKT2, AKT3, MTOR, RPTOR, RICTOR, TSC1, TSC2, RHEB

2. Suggested experimental readouts

For phospho-antibodies, pair with total protein, time-course stimulation, and controls; for IF, optimize fixation and clone selection.

  • p-SMAD2 / p-SMAD3 (sites depend on clone datasheet, e.g., Ser465/467)
  • Total SMAD2/3/4; nuclear/cytoplasmic distribution (fractionation or IF)
  • E-cadherin / N-cadherin / Vimentin (EMT panel)
  • Collagen I (COL1A1), α-SMA (ACTA2)—fibrosis / myofibroblast readouts
  • CD31 + α-SMA—pericyte/stroma interactions (model-dependent)
  • IFNγ signatures, FoxP3, CD8 (immune-suppressive TME pairing, project-dependent)

3. TGF-β vs BMP / Activin / Nodal branches

Ligand (examples)Type I receptor biasR-SMADNotes
TGF-β / Activin / NodalALK4 / ALK5 / ALK7SMAD2/3 (+ SMAD4)Sensitive to SB431542 / A83-01; do not conflate with BMP.
BMP / GDFALK1/2/3/6 等（语境依赖）SMAD1/5/8 (+ SMAD4)Parallel branch; pick inhibitors per ligand context.

4. Context dependence: cancer & TME

  • Epithelial phase: TGF-β often enforces growth arrest / pro-apoptotic programs—pair p-SMAD with cyclins/CDKs.
  • Progression / mesenchymal: EMT, matrix stiffening, immunosuppressive myeloid/Treg axes often couple to TGF-β.
  • SMAD4−/−: In SMAD4-null contexts (e.g., PDAC), TGF-β can shift pro-invasive—annotate genotypes.

TGF-β/Smad–related antibodies (curated)

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5. Product lines & on-site search

Primary & phospho antibodies

TGFB1, TGFBR1/2, SMAD2/3/4/7, p-SMAD2/3, SNAIL, α-SMA, Collagen I, Endoglin—WB/IHC/IF/FC as applicable.

Recombinant proteins / cytokines

Recombinant TGF-β1/2/3 for stimulation; BMP ligands for branch controls or competition (project-dependent).

Functional reagents & quantification

Neutralizing antibodies, soluble traps/Fc fusions (availability-dependent), species-matched TGF-β1 ELISAs—follow datasheets and ethics.

6. Inhibitors & tool compounds (summary)

For research use; follow lab SOP, compound datasheets, and ethics approvals.

SB431542

ALK4/5/7; canonical TGF-β receptor blockade.

LY2157299 (Galunisertib)

ALK5; clinical/clinical-stage TGF-β axis probe.

A83-01

ALK4/5/7; common in PSC/organoid workflows.

RepSox

ALK4/5/7; PSC/organoid TGF-β/Activin/Nodal suppression.

EW-7197

Oral selective ALK5 inhibitor; fibrosis/tumor controls.

LY3200882

Highly selective TGFBR1; immune–stroma studies.

SIS3

SMAD3 transcriptional interface disruptor (tool).

Halofuginone

Smad3 phospho inhibition; fibrosis readouts.

7. Pathway schematic

TGF-β / Smad canonical schematic
TGF-β/Smad pathway schematic
Legend
  1. Ligand–type II–type I (ALK5) assembly
  2. R-SMAD C-terminal phosphorylation
  3. Complex with SMAD4 and nuclear entry
  4. Transcriptional regulation & feedback (SMAD7, etc.)

8. Pathway biology overview

The TGF-β superfamily governs development, repair, and immune tolerance; in cancer it can enforce epithelial restraint yet promote late-stage invasion—interpret with genotype, stroma, and immune composition.

  • Fibrosis: fibroblast activation & collagen deposition (liver/lung/kidney models)
  • Immunity: crosstalk with Tregs, effector T cells, MDSC-like programs

9. Related pathways on this site

MAPK/ERK (non-canonical TAK1–MAPK)Angiogenesis (Endoglin, etc.)Cell cycleApoptosisWnt/β-cateninNF-κBJAK-STATPI3K/Akt/mTOR

10. External databases & modification resources

11. References

Receptors & SMAD mechanisms

  • • Shi Y, Massagué J. (2003). Cell. 113(6):685-96.
  • • Massagué J, Sheppard D. (2017). Nat Rev Mol Cell Biol. 18(7):436-454.

Tumor microenvironment & targeting

  • • Pickup M, Novitskiy S, Moses HL. (2013). Nat Rev Cancer. 13(11):788-99.
  • • Herbertz S, et al. (2015). Drug Discov Today. 20(7):787-97.