Affinage

TGFBR1

TGF-beta receptor type-1 · UniProt P36897

Length
503 aa
Mass
56.0 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGFBR1 (ALK5) is a transmembrane serine/threonine kinase type I receptor that transduces TGF-β family signals to control cell proliferation, epithelial-to-mesenchymal transition, fibrosis, vascular homeostasis, and tissue morphogenesis across virtually all organ systems. Upon ligand engagement — including TGF-β1–3, activins, GDF-15, and GDNF — ALK5 forms a heterotetrameric complex with TGFBR2 and accessory co-receptors (endoglin, betaglycan, neuropilin-1, biglycan, CD147) to phosphorylate canonical Smad2/3 and, through its L45 loop, non-canonical Smad1/5, while also activating PI3K, p38 MAPK, and ERK pathways in a context-dependent manner (PMID:19096363, PMID:21478266, PMID:31171625, PMID:18333754, PMID:27235139). ALK5 additionally functions as a ligand-independent mechanosensor in endothelial cells, where shear stress activates an ALK5–Shc pathway to drive endothelial-to-mesenchymal transition and atherosclerosis (PMID:34244146). Loss-of-function mutations in TGFBR1 cause Loeys-Dietz syndrome, an aortic aneurysm disorder in which paradoxical compensatory upregulation of TGF-β signaling occurs in affected tissues (PMID:15731757).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Constitutive ALK5 activation in embryonic myocardium demonstrated that this receptor controls cardiac myocyte proliferation, establishing ALK5 as a direct regulator of cell cycle exit through p21 induction during heart development.

    Evidence Transgenic mice expressing constitutively active ALK5 in myocardium, cardiac phenotyping and p21 immunostaining

    PMID:9676193

    Open questions at the time
    • Endogenous ligand context not defined
    • Direct transcriptional mechanism linking ALK5 to p21 not resolved
    • No loss-of-function complement at this stage
  2. 2002 High

    The development of SB-431542 as a selective ALK5/ALK4/ALK7 kinase inhibitor provided definitive pharmacological evidence that ALK5 kinase activity is required specifically for TGF-β/activin–Smad signaling but dispensable for BMP, ERK, JNK, and p38 pathways, establishing the selectivity framework for the field.

    Evidence In vitro kinase assays with selectivity profiling, cell-based reporter assays across multiple pathways

    PMID:12065756

    Open questions at the time
    • In vivo selectivity not addressed
    • Potential off-target kinase effects at higher concentrations not fully profiled
  3. 2004 High

    Genetic rescue/loss-of-function experiments in mouse palate demonstrated that ALK5 kinase activity and its Smad-binding capacity are both essential for TGF-β3-driven palatal fusion, establishing Smad-dependent ALK5 signaling as required for epithelial sheet fusion.

    Evidence Conditional genetic rescue with constitutively active and Smad-signaling-deficient ALK5 mutants in palatal organ cultures

    PMID:14729481

    Open questions at the time
    • Identity of specific Smad (Smad2 vs Smad3) required not resolved
    • Downstream transcriptional targets mediating fusion not identified
  4. 2005 High

    Identification of TGFBR1 mutations as the cause of Loeys-Dietz syndrome revealed a paradox: loss-of-function receptor mutations lead to compensatory upregulation of TGF-β signaling (increased pSmad2, collagen, CTGF) in patient tissues, redefining how receptor haploinsufficiency is understood in vascular disease.

    Evidence Patient-derived cell signaling assays, tissue immunostaining for pSmad2, collagen and CTGF expression in affected individuals

    PMID:15731757

    Open questions at the time
    • Molecular mechanism of paradoxical signaling upregulation not defined
    • Whether the paradox involves alternative type I receptors not resolved
  5. 2005 High

    Akt was shown to suppress ALK5-mediated Smad3 (but not Smad2) phosphorylation via mTOR, establishing a cross-talk node where PI3K/Akt/mTOR selectively modulates which Smad arm ALK5 activates.

    Evidence siRNA, constitutively active ALK5, rapamycin treatment, and co-immunoprecipitation in epithelial cells

    PMID:16362038

    Open questions at the time
    • Direct mTOR substrate mediating Smad3-specific inhibition not identified
    • Whether this selectivity operates in vivo not tested
  6. 2008 High

    ALK5 was shown to phosphorylate BMP-associated Smad1/5 in addition to canonical Smad2/3, with the L45 loop required for this non-canonical activity; Smad1/5 activation proved essential for TGF-β-induced migration, broadening ALK5's substrate repertoire beyond its canonical effectors.

    Evidence shRNA-resistant ALK5 mutant rescue in depleted cells, in vitro kinase assays, Smad1/5 co-depletion migration assays

    PMID:19096363

    Open questions at the time
    • Structural basis for L45 loop specificity toward Smad1/5 not resolved
    • Whether Smad1/5 activation by ALK5 occurs independently of BMP type I receptors in all contexts unclear
  7. 2008 High

    Lineage-specific conditional knockouts established that ALK5 is cell-autonomously required for EMT in both endocardium and epicardium during heart development, while receptor complex studies in chondrocytes revealed that ALK5 and ALK1 form an integrated signaling complex with opposing transcriptional outputs.

    Evidence Multiple Cre-loxP conditional knockouts (Tie2-Cre, Gata5-Cre, Nkx2.5-Cre), explant EMT assays, reciprocal co-immunoprecipitation in chondrocytes

    PMID:18333754 PMID:18718461

    Open questions at the time
    • How ALK1/ALK5 balance is regulated within the same complex not defined
    • Whether ALK5 EMT function in cardiac cells requires Smad2/3 or Smad1/5 not distinguished
  8. 2011 Medium

    In monocytes, ALK5 was found to drive TGF-β1-induced migration through PI3K and p38 MAPK independently of Smad2/3, establishing that ALK5 engages non-canonical signaling arms for chemotaxis in immune cells.

    Evidence ALK5 pharmacological inhibition, siRNA knockdown of Smad2/Smad3, pathway inhibitors, monocyte chemotaxis assays

    PMID:21478266

    Open questions at the time
    • Direct ALK5 substrate linking to PI3K/p38 in monocytes not identified
    • Whether non-canonical signaling requires TGFBR2 not tested
  9. 2015 Medium

    Beclin 1 was identified as a regulator of ALK5 surface availability by recruiting the retromer complex to promote ALK5 recycling through Rab11+ endosomes in neurons, revealing that receptor trafficking is a key regulatory layer for TGF-β signaling competence.

    Evidence Co-immunoprecipitation of beclin 1 with ALK5 and retromer, subcellular fractionation, beclin 1/VPS34/UVRAG knockdown with signaling readouts

    PMID:26692002

    Open questions at the time
    • Whether beclin 1-dependent recycling operates outside neurons not tested
    • Ubiquitination state of ALK5 during recycling not examined
  10. 2016 High

    Smooth muscle cell-specific Tgfbr1 deletion in adult mice caused lethal aortic aneurysm with 100% penetrance, driven by derepressed ERK and AngII/AT1R signaling — both preventable by pharmacological blockade — demonstrating ALK5 as a tonic suppressor of pathological vascular remodeling pathways.

    Evidence Inducible Myh11-Cre SMC-specific KO, double KO with Tgfbr2, pharmacological rescue with ERK inhibitor and AT1R blocker

    PMID:27739498

    Open questions at the time
    • How ALK5 loss derepresses AngII/AT1R signaling molecularly not defined
    • Whether this mechanism explains Loeys-Dietz aortic pathology not directly tested
  11. 2019 High

    GDNF was identified as a non-canonical ALK5 ligand that binds directly via His39/Asp76 residues and activates Smad2/3 to drive hepatic stellate cell activation and liver fibrosis, expanding the ligand repertoire of ALK5 beyond classical TGF-β superfamily members.

    Evidence Surface plasmon resonance, mutagenesis of binding residues, co-immunoprecipitation, in vivo GDNF overexpression/knockdown

    PMID:31171625

    Open questions at the time
    • Whether GDNF-ALK5 binding requires TGFBR2 or a co-receptor not fully resolved
    • Structural basis of GDNF-ALK5 complex not determined
  12. 2021 High

    ALK5 was established as a ligand-independent mechanosensor: shear stress activates ALK5 via the Shc adaptor to drive EndMT and atherosclerosis independently of TGF-β ligands and other known mechanosensors, revealing a fundamentally new activation mode for this receptor.

    Evidence Endothelial-specific ALK5 depletion, reconstitution experiments, tensional force assays, genetic Shc targeting, in vivo atherosclerosis model

    PMID:34244146

    Open questions at the time
    • How mechanical force is transmitted to ALK5 kinase domain without ligand not resolved
    • Whether mechanosensory function requires TGFBR2 heterodimerization not tested
  13. 2021 High

    A pathogenic TGFBR1 variant was shown to disrupt SMAD3 and AKT activation selectively in cardiovascular progenitor-derived but not neural crest-derived smooth muscle cells, establishing that TGFBR1 signaling output is lineage-dependent and explaining tissue-selective vascular disease.

    Evidence Isogenic CRISPR-corrected hiPSC lines, lineage-specific SMC differentiation, scRNA-seq, mechanical testing, activin A/rapamycin rescue

    PMID:34346740

    Open questions at the time
    • Molecular basis for lineage-specific signaling difference not identified
    • Whether lineage specificity is intrinsic to receptor or to downstream effector expression unclear
  14. 2022 High

    Mitochondrial dysfunction was shown to redirect SMAD2 to mitochondria where MAPK-mediated phosphorylation enhances ALK5-SMAD2 signaling, causing retinal arteriovenous malformations — a mechanism preventable by ALK5 inhibition — linking organelle stress to pathological ALK5 output.

    Evidence Three independent endothelial-specific conditional KO models (Tfam, Cox10, Trx2), scRNA-seq, ALK5 inhibitor and SMAD2 genetic rescue

    PMID:36496409

    Open questions at the time
    • How mitochondrial SMAD2 is re-routed to ALK5 signaling not mechanistically defined
    • Whether this mitochondrial-ALK5 axis operates in non-retinal vasculature not tested
  15. 2023 Medium

    RCN3 was identified as a cytoplasmic sequestrant of EZH2, relieving H3K27me3 epigenetic repression at the TGFBR1 locus to sustain receptor expression in fibrotic fibroblasts, closing a TGF-β1→RCN3→TGFBR1 positive feedback loop that perpetuates fibrosis.

    Evidence BioID proximity labeling, ChIP for H3K27me3 at TGFBR1 locus, fibroblast-specific Rcn3 knockdown mice, bleomycin fibrosis model

    PMID:37710230

    Open questions at the time
    • Whether this feedback loop operates in non-pulmonary fibrosis contexts not tested
    • Direct EZH2 binding to TGFBR1 promoter not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how ALK5 senses mechanical force at the structural level without ligand engagement; what determines lineage-specific signaling output from the same receptor; and how the balance between canonical Smad2/3, non-canonical Smad1/5, and Smad-independent pathways is set in different cell types.
  • No structural model of force-activated ALK5
  • Molecular determinants of lineage-specific pathway selection unknown
  • Integrated quantitative model of ALK5 pathway switching absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2 R-HSA-1474165 Reproduction 1
Partners
BECN1BSGENGGADD45BNRP1SMAD2SMAD3TGFBR2
Complex memberships
ALK1/ALK5/TGFBR2/endoglin complexTGFBR1/TGFBR2 heterotetramer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SB-431542 was identified as a potent and selective inhibitor of the ALK5 (TGFBR1) kinase, also inhibiting the closely related ALK4 and ALK7, but not other more divergent ALK family members (BMP type I receptors). It selectively blocks TGF-β and activin signaling (Smad pathway) without affecting ERK, JNK, p38 MAPK, or BMP signaling. In vitro kinase assays, cell-based reporter assays, pathway activation measurements Molecular pharmacology High 12065756
2004 TGF-β type I receptor TGFBR1 (ALK5) is a serine/threonine kinase whose ATP-binding site structure was resolved, enabling structure-based design of selective inhibitors; structural studies provided insight into inhibitor potency and selectivity. Structural studies, target-hopping, HTS, virtual screening converging on a kinase pharmacophore Current opinion in drug discovery & development Medium 15338953
2005 TGFBR1 (ALK5) mutations in Loeys-Dietz syndrome result in receptors incapable of TGF-β signal propagation, yet paradoxically tissues from affected individuals show increased nuclear phospho-Smad2 and increased collagen/CTGF expression, indicating a compensatory upregulation of TGF-β signaling in vivo. Patient-derived cell signaling assays, tissue immunostaining for pSmad2, collagen and CTGF expression analysis Nature genetics High 15731757
2005 A-83-01, a selective ALK5 kinase inhibitor, blocks TGF-β-induced phosphorylation of Smad2/3, transcriptional responses, growth inhibition, and epithelial-to-mesenchymal transition (EMT), confirming that ALK5 kinase activity is required for these TGF-β responses. Reporter assays, Western blot for pSmad2/3, EMT assays, cell growth assays Cancer science High 16271073
2005 Akt suppresses TGFBR1 (ALK5)-mediated Smad3 (but not Smad2) phosphorylation through an mTOR-dependent mechanism; constitutively active ALK5 (FKBP12-resistant) was used to demonstrate that mTOR mediates Akt1 suppression of Smad3 activation downstream of ALK5. siRNA, adenoviral expression of constitutively active ALK5, rapamycin treatment, co-immunoprecipitation, Western blot The EMBO journal High 16362038
2005 TGFBR1*6A, a common polymorphic variant of TGFBR1 with a 9-bp in-frame deletion, is capable of switching TGF-β growth-inhibitory signals into growth-stimulatory signals when stably transfected into MCF-7 breast cancer cells; the functional effect is mediated by the signal sequence, not the mature receptor domain. In vitro translation assays, stable transfection, cell proliferation assays, somatic acquisition analysis JAMA Medium 16204663
2004 ALK5 (TGFBR1) is required for Tgf-β3-driven palatal fusion through the Smad2-dependent signaling pathway; activation of ALK5 in Tgf-β3-null palatal epithelium rescues fusion, while inactivation blocks it. A kinase-active but Smad-binding-incompetent ALK5 mutant cannot rescue fusion, demonstrating Smad-dependence. Conditional mouse genetic rescue/loss-of-function experiments, constitutively active and Smad-signaling-deficient ALK5 mutants in palatal organ cultures Developmental biology High 14729481
2008 TGFBR1 (ALK5) kinase activity and its L45 loop motif are required for TGF-β-stimulated phosphorylation of Smad1 and Smad5 (typically BMP-associated R-Smads), in addition to canonical Smad2/3. This non-canonical Smad1/5 phosphorylation via ALK5 is essential for TGF-β-stimulated cell migration in mammary epithelial cells. shRNA-resistant ALK5 mutant rescue in ALK5-depleted cells, in vitro kinase assays, Smad1/5 co-depletion migration assays The EMBO journal High 19096363
2008 In endothelial cells, ALK5 mediates TGF-β-induced endothelin-1 (ET-1) expression preferentially through the ALK5/Smad3 pathway, and this ET-1 production mediates the anti-angiogenic (anti-migratory and anti-proliferative) effects of TGF-β in an autocrine manner. Specific ALK5 pharmacological inhibition, ET receptor antagonism, migration and proliferation assays Journal of cell science Medium 17376964
2008 ALK1 and ALK5 form a complex with each other and with TGF-β type II receptor, endoglin, and betaglycan in human chondrocytes. ALK1 and ALK5 have opposing functions: ALK5 is essential for Smad3 phosphorylation and potentiates ECM expression, while ALK1 inhibits Smad3-driven transcription and ECM expression. Affinity labeling/immunoprecipitation, co-immunoprecipitation, Western blot for pSmad1/5 and pSmad3, promoter/luciferase assays Journal of bone and mineral research High 18333754
2008 Conditional endocardial knockout of Alk5 (using Tie2-Cre) abolishes TGF-β-induced epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo during cardiac development; epicardial Alk5 deletion disrupts epicardial-myocardial cell-cell interactions and blocks epicardial EMT, revealing cell-autonomous roles in cardiac EMT. Conditional Cre-loxP mouse knockouts (Tie2-Cre, Nkx2.5-Cre, Gata5-Cre), in vitro explant EMT assays Developmental biology High 18718461
2008 TGFBR1*6A enhances MCF-7 breast cancer cell migration and invasion in a TGF-β signaling-independent manner, through downregulation of ARHGAP5 (a RhoA-GAP), leading to increased RhoA and ERK activation; a kinase-inactivated TGFBR1*6A construct produced the same effect. Stable transfection with wild-type TGFBR1, TGFBR1*6A, and kinase-dead TGFBR1*6A; gene expression profiling; RhoA activation assay; migration/invasion assays Cancer research Medium 18316594
2008 Loss of endoglin or Alk5 (by siRNA or specific kinase inhibitor) directly blocks epithelial-to-mesenchymal transformation (EMT) and reduces expression of EMT markers (slug, runx2, RhoA, latrophilin-2) during cardiac valve formation; endoglin and Alk5 associate with each other. Antisense DNA/siRNA knockdown, pharmacological kinase inhibition (HTS466284), BrdU proliferation assays, EMT marker expression Developmental biology Medium 17250821
1998 A constitutively activated ALK5 mutant (L193A, P194A, T204D) directed to embryonic myocardium arrests cardiac looping morphogenesis and causes hypoplastic heart tube, associated with precocious induction of p21 (cyclin-dependent kinase inhibitor), suggesting ALK5 controls cardiac myocyte proliferation. Transgenic mouse overexpression of constitutively active ALK5 in myocardium, cardiac phenotyping, p21 immunostaining Developmental biology Medium 9676193
2010 Deletion of Alk5 in embryonic lung epithelium (Gata5-Cre) blocks Clara cell differentiation; Alk5-regulated Hes1 expression is downstream of Pten and MEK/ERK and PI3K/AKT pathways. Loss of Alk5 stimulates Pten expression and inhibits ERK phosphorylation, revealing an ALK5-Pten-ERK/AKT-Hes1 axis controlling Clara cell fate. Conditional Cre-loxP knockout, in vivo and in vitro gene expression analysis, pathway inhibitor studies Development Medium 20147383
2011 TGF-β1-induced monocyte migration requires ALK5 kinase activity and downstream signaling via PI3K and p38 MAPK, but not SMAD2, SMAD3, AKT, or ERK1/2; individual genetic knockdown of Smad2 or Smad3 did not affect monocyte migration toward TGF-β1. ALK5 pharmacological inhibition, siRNA knockdown of Smad2/Smad3, PI3K/AKT/p38/ERK inhibitors, monocyte chemotaxis assays Cardiovascular research Medium 21478266
2015 Beclin 1 is required for recycling of TGFBR1 (ALK5) to the cell surface in neurons; beclin 1 recruits the retromer complex to ALK5 and facilitates its localization to Rab11+ recycling endosomes. Decreased beclin 1, or its binding partners VPS34 and UVRAG, impairs TGF-β signaling. Co-immunoprecipitation (beclin 1 with ALK5 and retromer), subcellular fractionation/immunofluorescence for Rab11+ endosomes, beclin 1/VPS34/UVRAG knockdown with TGF-β signaling readouts Molecular neurodegeneration Medium 26692002
2015 Neuropilin-1 (Nrp1) suppresses Smad2/3 activation by limiting ALK5 (and ALK1) signaling in endothelial cells; Notch downregulates Nrp1, thereby relieving inhibition of ALK5 and driving stalk-cell behavior during angiogenesis. Genetic endothelial-specific Nrp1 loss-of-function, epistasis with Notch and ALK5/ALK1 pathway, Smad2/3 phosphorylation measurements Nature communications Medium 26081042
2016 GDF-15 inhibits chemokine-induced leukocyte integrin activation and neutrophil diapedesis via the ALK5/TGF-βRII heterodimer receptor complex; this signaling interferes with Rap-1 activation (via CalDAG-GEF1 and Cdc42), providing a rapid anti-inflammatory mechanism. Small-molecule inhibitors, siRNA, antibody blockade, conditional gene-deficient mice (ALK5 and TGF-βRII neutrophil-specific knockouts), intravital microscopy Blood High 27235139
2016 Smooth muscle cell-specific deletion of Tgfbr1 (but not Tgfbr2 alone) in adult mice causes rapid and severe aortic aneurysmal degeneration with 100% penetrance via multiple deleterious pathways including abnormal TGFBR2 activity, ERK phosphorylation, and AngII/AT1R signaling; ERK inhibition or AT1R blockade prevents aneurysm formation in Tgfbr1-deficient aortas. Inducible Cre-loxP SMC-specific knockout (Myh11-Cre), double KO, pharmacological epistasis (ERK inhibitor, AT1R blocker), aortic phenotyping Scientific reports High 27739498
2017 Biglycan forms a complex with either TGF-β1 or ALK5 in vascular endothelial cells, intensifying pSmad2/3 signaling and resulting in decreased syndecan-4 expression; biglycan siRNA knockdown reduces Smad2/3 phosphorylation. siRNA knockdown of biglycan, co-immunoprecipitation of biglycan with TGF-β1 and ALK5, Smad2/3 phosphorylation Western blot, syndecan-4 expression analysis Journal of cellular biochemistry Medium 27585241
2017 Lumican C-terminal peptide (LumC13) binds directly to ALK5 (TGFBR1) to form a stable complex, promoting corneal epithelial cell migration and wound healing; minimal binding amino acids were identified by in silico design and validated in vitro and in vivo. In silico molecular docking/dynamics, in vitro cell migration assays, in vivo corneal wound healing, binding assays Scientific reports Medium 28181591
2018 CYLD deubiquitinating enzyme loss promotes stabilization of ALK5 (TGFBR1) protein in a cell-autonomous manner, leading to enhanced TGF-β signaling and acquisition of invasive mesenchymal properties in oral squamous cell carcinoma; ALK5 inhibition completely blocks these invasive phenotypes. siRNA knockdown of CYLD, ALK5 protein stability assay, ALK5 inhibitor blocking of invasion phenotype, Smad3 phosphorylation as readout The Journal of pathology Medium 29235674
2019 GDNF binds directly to ALK5 at His39 and Asp76 residues and activates downstream Smad2/3 signaling to promote hepatic stellate cell activation and liver fibrosis; GDNF signaling in this context is through ALK5, not through its canonical GFRα1 receptor. Surface plasmon resonance (SPR), molecular docking, mutagenesis, co-immunoprecipitation, confocal colocalization, in vivo GDNF overexpression/knockdown/antibody blocking Gut High 31171625
2019 Uterine conditional knockout of ALK5 (progesterone receptor-Cre) in mice causes metastatic endometrial adenocarcinoma in mated animals, establishing that TGFBR1/ALK5-mediated TGF-β signaling in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum regeneration. Conditional Cre-loxP knockout (progesterone receptor-Cre), tumor histopathology, lung metastasis analysis, estrogen receptor/progesterone receptor expression Proceedings of the National Academy of Sciences High 30655341
2019 ALK5 overexpression after cerebral ischemia/reperfusion promotes neurogenesis and functional recovery via Smad2/3 phosphorylation; ALK5 physically interacts with (co-immunoprecipitates) Gadd45b and mediates its protein levels, linking ALK5 signaling to axonal plasticity. Lentiviral ALK5 knockdown/overexpression in MCAO/R rat model, co-immunoprecipitation of ALK5 with Gadd45b, Smad2/3 phosphorylation analysis Cell death & disease Medium 31043581
2021 A pathogenic TGFBR1 variant causes lineage-specific SMC defects: it selectively disrupts SMAD3 and AKT activation in cardiovascular progenitor cell (CPC)-derived SMCs but not neural crest-derived SMCs. Combination treatment with activin A and rapamycin rescues the contractile gene expression and mechanical properties of mutant CPC-SMCs. hiPSC with CRISPR-Cas9 gene editing, lineage-specific SMC differentiation, single-cell RNA-seq, Western blot, tissue construct mechanical testing Circulation High 34346740
2021 Mechanical shear stress signals through ALK5 (TGFBR1) via a Shc adaptor pathway to induce endothelial-to-mesenchymal transition (EndMT) and atherosclerosis; ALK5 depletion abrogates shear stress-induced EndMT, and this mechanosensory function is independent of other known mechanosensors and independent of canonical TGF-β ligand engagement. Endothelial-specific ALK5 depletion, reconstitution experiments, tensional force assays, genetic targeting of Shc in vivo, EndMT and atherosclerosis phenotyping Science advances High 34244146
2021 TGF-β1 induces ZIP8 metal transporter expression via the ALK5-Smad2/3 signaling pathway (with Smad3-mediated induction also involving p38 MAPK), increasing cadmium uptake and cytotoxicity in vascular endothelial cells. ALK5-specific inhibitor, Smad2/Smad3 siRNA knockdown, ZIP8 expression and cadmium uptake assays International journal of molecular sciences Medium 35008873
2022 Simultaneous muscle-specific knockout of both TGF-β type I receptors Tgfbr1 and Acvr1b in mice induces substantial myofibre hypertrophy via increased Akt/p70S6K phosphorylation and reduced E3 ligase expression, and improves muscle regeneration by increasing satellite cells and macrophages; single receptor knockout of Tgfbr1 alone is insufficient for hypertrophy. Double conditional muscle-specific knockout (Tgfbr1 and Acvr1b), single KO comparisons, Akt/p70S6K phosphorylation, cardiotoxin-injury regeneration model eLife High 35323108
2022 Mitochondrial dysfunction (via TFAM, COX10, or TRX2 depletion in endothelial cells) induces mitochondrial localization and MAPK-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling and retinal arteriovenous malformations; pharmacological ALK5 blockade or genetic SMAD2 deficiency prevents these vascular defects. Endothelial-specific conditional KO mice (Tfam, Cox10, Trx2), scRNA-seq, ALK5 inhibitor rescue, SMAD2 genetic KO rescue, subcellular fractionation showing mitochondrial SMAD2 Nature communications High 36496409
2023 NRP1 (neuropilin-1) interacts with TGFBR2 through their cytoplasmic domains and activates the TGFBR1/TGFBR2 receptor complex, facilitating macropinocytosis-mediated KSHV internalization via Cdc42 and Rac1 small GTPases in mesenchymal stem cells. NRP1 knockout/overexpression, shRNA screening, Co-IP of NRP1 with TGFBR2, soluble NRP1 blocking assay, Cdc42/Rac1 functional assays Science advances Medium 37224259
2023 CD147 directly binds to ALK5 (TGFBR1), promoting ALK5 activation and endocytosis to induce SMAD2/3 phosphorylation and nuclear translocation in cardiac fibroblasts; N-glycosylation by GNT-V prevents ubiquitin-proteasome-dependent CD147 degradation under high-glucose conditions, thereby amplifying ALK5 signaling. Co-immunoprecipitation of CD147 with ALK5, AAV9-mediated cardiac-specific CD147 silencing/overexpression, ALK5 endocytosis assay, GNT-V glycosylation analysis International journal of biological sciences Medium 36594096
2023 RCN3 maintains persistent TGFBR1 expression in IPF lung fibroblasts by sequestering EZH2 methyltransferase in the cytoplasm, relieving EZH2-H3K27me3 epigenetic repression of the TGFBR1 gene; TGF-β1 upregulates RCN3, creating a positive feedback loop (TGFβ1-RCN3-TGFBR1) to sustain fibroblast activation. BioID proximity labeling (RCN3-EZH2 interaction), epigenetic ChIP analysis (H3K27me3 at TGFBR1 locus), Rcn3 fibroblast-specific knockdown mouse model, in vivo bleomycin fibrosis model Respiratory research Medium 37710230
2017 TGF-β/ALK5 signaling in articular chondrocytes regulates PRG4 (lubricin) expression partially through the protein kinase A (PKA)-CREB signaling pathway; cartilage-specific inducible Alk5 deletion causes progressive osteoarthritis-like degeneration with decreased PRG4 and increased catabolic factor production. Inducible cartilage-specific Alk5 conditional KO mice, PKA/CREB pathway inhibitors, PRG4 expression analysis by qRT-PCR/Western blot/IHC Osteoarthritis and cartilage Medium 28716756

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Molecular pharmacology 1442 12065756
2005 A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature genetics 1288 15731757
2005 The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer science 271 16271073
2005 Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. The EMBO journal 155 16362038
2008 TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. The EMBO journal 151 19096363
2009 Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. Journal of medical genetics 145 19542084
2006 TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Human mutation 144 16799921
2015 Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nature communications 136 26081042
2008 Signaling via the Tgf-beta type I receptor Alk5 in heart development. Developmental biology 133 18718461
2008 ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 132 18333754
2008 Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. American journal of respiratory and critical care medicine 129 18202349
2008 Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science (New York, N.Y.) 119 18703712
2021 M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway. Cell death and differentiation 113 34628486
1996 Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. International journal of cancer 101 8760600
2008 L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. Journal of cell science 100 18303046
2014 EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Molecular cancer therapeutics 92 24817629
2016 GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer. Blood 91 27235139
2018 Linc00462 promotes pancreatic cancer invasiveness through the miR-665/TGFBR1-TGFBR2/SMAD2/3 pathway. Cell death & disease 87 29899418
2007 Signaling by ALK5 mediates TGF-beta-induced ET-1 expression in endothelial cells: a role for migration and proliferation. Journal of cell science 85 17376964
2006 Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Human mutation 85 16791849
2022 Calycosin reduces myocardial fibrosis and improves cardiac function in post-myocardial infarction mice by suppressing TGFBR1 signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 79 35752078
2005 Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 79 16204663
2004 Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway. Developmental biology 76 14729481
2014 Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma. Neuro-oncology 69 25165192
2006 Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation. Developmental biology 64 17250821
2021 Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway. Science advances 63 34244146
2016 Naringenin Ameliorated Kidney Injury through Let-7a/TGFBR1 Signaling in Diabetic Nephropathy. Journal of diabetes research 60 27446963
2016 Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events. Scientific reports 58 27739498
2018 miR-22 regulates C2C12 myoblast proliferation and differentiation by targeting TGFBR1. European journal of cell biology 55 29588073
2019 ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b. Cell death & disease 52 31043581
2018 Luteolin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting TGFBR1 Signaling. Frontiers in pharmacology 52 30298006
2016 TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial-mesenchymal transition. Experimental & molecular medicine 52 27885255
2007 TGFB1 and TGFBR1 polymorphisms and breast cancer risk in the Nurses' Health Study. BMC cancer 50 17848193
2018 Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer. International journal of molecular sciences 47 29795022
2010 Signaling via Alk5 controls the ontogeny of lung Clara cells. Development (Cambridge, England) 47 20147383
2008 TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation. Cancer research 47 18316594
2019 Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling. Gut 44 31171625
2018 Long non-coding RNA SBF2-AS1 promotes hepatocellular carcinoma progression through regulation of miR-140-5p-TGFBR1 pathway. Biochemical and biophysical research communications 44 30115383
2017 Efficacy of ALK5 inhibition in myelofibrosis. JCI insight 44 28405618
2011 TGFBR1 signaling and breast cancer. Journal of mammary gland biology and neoplasia 44 21461994
2018 MicroRNA-98-5p inhibits proliferation and metastasis in non-small cell lung cancer by targeting TGFBR1. International journal of oncology 43 30387848
2018 miR-3607-3p suppresses non-small cell lung cancer (NSCLC) by targeting TGFBR1 and CCNE2. PLoS genetics 43 30557355
2004 Transforming the TGFbeta pathway: convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5). Current opinion in drug discovery & development 42 15338953
2021 hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1 Variant, and Its Therapeutic Implications for Loeys-Dietz Syndrome. Circulation 40 34346740
2019 Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma. Proceedings of the National Academy of Sciences of the United States of America 39 30655341
2015 Beclin 1 regulates neuronal transforming growth factor-β signaling by mediating recycling of the type I receptor ALK5. Molecular neurodegeneration 39 26692002
2011 TGF-β1/ALK5-induced monocyte migration involves PI3K and p38 pathways and is not negatively affected by diabetes mellitus. Cardiovascular research 39 21478266
2011 EW-7195, a novel inhibitor of ALK5 kinase inhibits EMT and breast cancer metastasis to lung. European journal of cancer (Oxford, England : 1990) 38 21852112
2004 An intronic variant of the TGFBR1 gene is associated with carcinomas of the kidney and bladder. International journal of cancer 38 15382067
2019 Let-7f-5p regulates TGFBR1 in glucocorticoid-inhibited osteoblast differentiation and ameliorates glucocorticoid-induced bone loss. International journal of biological sciences 36 31592234
2017 Lumican Peptides: Rational Design Targeting ALK5/TGFBRI. Scientific reports 36 28181591
2008 Absence of TGFBR1 and TGFBR2 mutations in patients with bicuspid aortic valve and aortic dilation. The American journal of cardiology 36 18721526
2019 Dysregulated miR-142, -33b and -423 in granulosa cells target TGFBR1 and SMAD7: a possible role in polycystic ovary syndrome. Molecular human reproduction 35 30865275
2022 High-Phosphate-Stimulated Macrophage-Derived Exosomes Promote Vascular Calcification via let-7b-5p/TGFBR1 Axis in Chronic Kidney Disease. Cells 34 36611957
2021 Taohong siwu decoction attenuates myocardial fibrosis by inhibiting fibrosis proliferation and collagen deposition via TGFBR1 signaling pathway. Journal of ethnopharmacology 34 33460756
1998 A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. Developmental biology 33 9676193
2018 miR-181a regulate porcine preadipocyte differentiation by targeting TGFBR1. Gene 32 30266501
2017 Biglycan Intensifies ALK5-Smad2/3 Signaling by TGF-β1 and Downregulates Syndecan-4 in Cultured Vascular Endothelial Cells. Journal of cellular biochemistry 31 27585241
2017 Cartilage-specific deletion of Alk5 gene results in a progressive osteoarthritis-like phenotype in mice. Osteoarthritis and cartilage 29 28716756
2016 Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC biology 29 26984772
2021 Myricetin suppresses the proliferation and migration of vascular smooth muscle cells and inhibits neointimal hyperplasia via suppressing TGFBR1 signaling pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 34500301
2018 Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. The Journal of pathology 28 29235674
2006 Inhibition of ALK5 as a new approach to treat liver fibrotic diseases. Drug news & perspectives 28 16628263
2019 The long noncoding RNA AK002107 negatively modulates miR-140-5p and targets TGFBR1 to induce epithelial-mesenchymal transition in hepatocellular carcinoma. Molecular oncology 27 30943320
2009 TGFBR1 haplotypes and risk of non-small-cell lung cancer. Cancer research 26 19690145
2007 Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clinical cancer research : an official journal of the American Association for Cancer Research 26 17575241
2023 Integrin β8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-β1/TGFBR1/Smad3 pathway in diabetic kidney disease. Translational research : the journal of laboratory and clinical medicine 25 37931653
2014 TGFBR1 and cancer susceptibility. Transactions of the American Clinical and Climatological Association 25 25125747
2023 Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis. Science advances 24 37224259
2010 ALK5 inhibition blocks TGFß-induced CCN2 expression in gingival fibroblasts. Journal of dental research 24 20924066
2001 The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. The Journal of pathology 22 11329144
2022 GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β-catenin and ALK5/SMAD2/3 pathways. Cell proliferation 21 35920128
2016 Galangin inhibits hypertrophic scar formation via ALK5/Smad2/3 signaling pathway. Molecular and cellular biochemistry 21 26728998
2023 TGFβ1-RCN3-TGFBR1 loop facilitates pulmonary fibrosis by orchestrating fibroblast activation. Respiratory research 20 37710230
2023 The long noncoding RNA THBS1-AS1 promotes cardiac fibroblast activation in cardiac fibrosis by regulating TGFBR1. JCI insight 19 36787190
2020 A Highly Selective Chemical Probe for Activin Receptor-like Kinases ALK4 and ALK5. ACS chemical biology 19 32176847
2019 miR-181a promotes porcine granulosa cell apoptosis by targeting TGFBR1 via the activin signaling pathway. Molecular and cellular endocrinology 19 31574295
2017 Fluoride Regulate Osteoblastic Transforming Growth Factor-β1 Signaling by Mediating Recycling of the Type I Receptor ALK5. PloS one 19 28125630
2012 Association between TGFBR1 polymorphisms and cancer risk: a meta-analysis of 35 case-control studies. PloS one 19 22905183
2017 Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway. Laboratory investigation; a journal of technical methods and pathology 18 28737766
2017 Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. Journal of vascular surgery 18 28847661
2010 Allele-specific expression of TGFBR1 in colon cancer patients. Carcinogenesis 18 20705955
2023 N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. International journal of biological sciences 17 36594096
2023 WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer. Cell death & disease 17 37443102
2022 Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors. Medicinal chemistry (Shariqah (United Arab Emirates)) 17 34182915
2022 Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration. eLife 17 35323108
2022 CircCAMTA1 facilitates atrial fibrosis by regulating the miR-214-3p/TGFBR1 axis in atrial fibrillation. Journal of molecular histology 17 36417034
2021 TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. International journal of molecular sciences 17 35008873
2016 Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors. JCI insight 17 27182558
2023 Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation. Bioorganic chemistry 16 37459824
2022 Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature communications 16 36496409
2021 Piperlongumine inhibits the growth of non-small cell lung cancer cells via the miR-34b-3p/TGFBR1 pathway. BMC complementary medicine and therapies 16 33413277
2021 Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors. European journal of medicinal chemistry 16 33677350
2021 GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression. Reproduction (Cambridge, England) 16 34432647
2017 Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury. Developmental neuroscience 16 28628913
2024 Blockade of endothelial adenosine receptor 2 A suppresses atherosclerosis in vivo through inhibiting CREB-ALK5-mediated endothelial to mesenchymal transition. Pharmacological research 15 38522762
2022 Igf2bp2 knockdown improves CCl4-induced liver fibrosis and TGF-β-activated mouse hepatic stellate cells by regulating Tgfbr1. International immunopharmacology 15 35820364
2018 Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors. Pulmonary pharmacology & therapeutics 15 30448291
2020 Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p. Communications biology 14 32581266
2009 TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk. British journal of cancer 14 19401691