Affinage

TGFBR1

TGF-beta receptor type-1 · UniProt P36897

Length
503 aa
Mass
56.0 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TGFBR1 (ALK5) is the type I transmembrane serine/threonine kinase receptor that transduces TGFβ-family ligand signals into canonical Smad-dependent transcriptional programs governing epithelial-mesenchymal transition, tissue morphogenesis, fibrosis, and growth control (PMID:10574705, PMID:14729481, PMID:32176847). Within the receptor complex it cooperates with TGFBR2 and accessory receptors and, in endothelial and chondrocyte contexts, recruits ALK1 and assembles with endoglin and betaglycan; ALK5 kinase activity is required for optimal ALK1 activation, and ALK1-Smad1/5 signaling reciprocally antagonizes the ALK5-Smad2/3 axis (PMID:14580334, PMID:18333754). Its principal catalytic output is phosphorylation of Smad2 and Smad3, demonstrated directly with selective kinase inhibition, driving EMT, collagen and ECM gene expression (PAI-1, fibronectin, type II collagen), and growth-inhibitory responses (PMID:10574705, PMID:18333754, PMID:32176847). Beyond this canonical axis ALK5 phosphorylates Smad1 and Smad5 through its kinase activity and L45 loop to promote cell migration, and basally phosphorylates the endoglin cytoplasmic domain at serines 646/649 to regulate Smad1/5/8 output (PMID:19096363, PMID:20042635). ALK5 acts as a dose-dependent tumor suppressor in intestine, uterus, and squamous epithelium through Smad-mediated growth control, with haploinsufficiency raising cyclin D1 and proliferation (PMID:19147584, PMID:30655341); loss of TGFBR1 can paradoxically unleash TGFBR2-ERK and angiotensin signaling, producing aortic aneurysm (PMID:27739498). In endothelium ALK5 functions as a mechanoreceptor that drives EndMT under disturbed shear stress via an ALK5-Shc pathway (PMID:34244146). Receptor abundance and activity are controlled post-translationally and epigenetically: CYLD deubiquitinase loss stabilizes ALK5 to enhance invasion (PMID:29235674), CD147 binds and promotes ALK5 activation and endocytosis (PMID:36594096), and a TGFβ1-RCN3 loop relieves EZH2-H3K27me3 repression of the TGFBR1 promoter to sustain its expression (PMID:37710230). Germline and somatic TGFBR1 mutations cause Loeys-Dietz syndrome, where mutant alleles paradoxically yield elevated tissue TGFβ signaling (PMID:15731757), and loss-of-function mutations cause multiple self-healing squamous epithelioma (Ferguson-Smith disease) in a digenic manner (PMID:33256177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established that TGFβ-induced EMT in epithelial cells is channeled specifically through ALK5 and its downstream Smad2/3/Smad4 module, defining the receptor's core transcriptional effector pathway.

    Evidence Adenoviral constitutively active ALK5 and dominant-negative constructs with Smad co-expression and cytoskeletal/E-cadherin readouts in mammary epithelial cells

    PMID:10574705

    Open questions at the time
    • Did not resolve which target genes mediate the cytoskeletal reorganization
    • Cooperative thresholds defined in vitro, not in vivo
  2. 2003 High

    Resolved how ALK5 integrates with ALK1 in endothelium, showing ALK5 kinase activity recruits and activates ALK1, which then opposes ALK5-Smad2/3 signaling — a reciprocal balance controlling endothelial behavior.

    Evidence ALK5-null endothelial cells, Co-IP complex formation, reporter and kinase assays

    PMID:14580334

    Open questions at the time
    • Stoichiometry of the ALK5/ALK1 complex not defined
    • How the balance is set in different vascular beds unclear
  3. 2004 High

    Demonstrated by domain-specific genetic rescue that Smad-dependent (not merely kinase) signaling downstream of ALK5 is required for a developmental fusion event, separating ALK5 kinase activity from its Smad-coupling function.

    Evidence Conditional rescue with activated/kinase-dead and Smad-deficient ALK5 mutants in Tgfβ3-null palatal explants

    PMID:14729481

    Open questions at the time
    • Smad-independent ALK5 outputs in this tissue not characterized
  4. 2005 High

    Connected TGFBR1 to human disease, showing Loeys-Dietz mutations paradoxically increase tissue TGFβ signaling despite reduced signal propagation in vitro, and that a cancer-associated 6A polymorphism can convert growth-inhibitory into growth-stimulatory signaling.

    Evidence Patient-derived tissues with phospho-Smad2/collagen/CTGF staining; in vitro translation and TGFβ proliferation assays in transfected cells

    PMID:15731757 PMID:16204663

    Open questions at the time
    • Mechanism reconciling reduced receptor activity with elevated tissue signaling unresolved
    • 6A signal-peptide effect on receptor processing not structurally defined
  5. 2006 High

    Defined non-overlapping in vivo roles by mapping ALK5 to medial/adventitial vascular layers and showing ALK5-null vascular smooth muscle defects distinct from ALK1-null lumen defects.

    Evidence Alk5-lacZ knockin reporter mice with comparative Alk5-null and Alk1-null phenotype analysis

    PMID:16344855

    Open questions at the time
    • Cell-type-specific contribution of ALK5 to SMC formation not dissected at the molecular level
  6. 2008 High

    Expanded ALK5's catalytic repertoire beyond Smad2/3 by showing its kinase activity and L45 loop phosphorylate Smad1/5 to drive migration, and that it directly phosphorylates the endoglin cytoplasmic tail to set Smad1/5/8 output.

    Evidence shRNA-resistant L45-loop ALK5 mutants with in vitro kinase and migration assays; site-directed mutagenesis of endoglin S646/S649 with Smad1/5/8 reporters

    PMID:18333754 PMID:19096363 PMID:20042635

    Open questions at the time
    • Structural basis of L45-mediated substrate selection not solved
    • Physiological contexts where Smad1/5 branch dominates not mapped
  7. 2009 High

    Established TGFBR1 as a dose-dependent intestinal tumor suppressor, linking receptor gene dosage to Smad phosphorylation, cyclin D1 levels, and proliferation.

    Evidence Tgfbr1+/- ; ApcMin/+ mice with tumor counts, Smad phospho-blots, cyclin D1 IHC, BrdU assays

    PMID:19147584

    Open questions at the time
    • Threshold of receptor activity defining tumor suppression vs promotion not quantified
  8. 2010 High

    Identified receptor-specific developmental functions of ALK5 distinct from TGFBR2, including neural-crest patterning via Gsc and lung Clara cell differentiation via a Pten/ERK/AKT-Hes1 mechanism.

    Evidence Side-by-side Wnt1-Cre Alk5 vs Tgfbr2 conditional KOs and Gata5-Cre lung KO with pathway and gene-expression analyses

    PMID:18572160 PMID:20147383

    Open questions at the time
    • How ALK5 signals independently of TGFBR2 in these tissues mechanistically unclear
    • Pten regulation by ALK5 not biochemically defined
  9. 2016 High

    Showed ALK5 loss in vascular smooth muscle drives aneurysm by de-repressing TGFBR2-ERK and AngII/AT1R signaling, revealing a homeostatic restraint function whose loss redirects signaling pathologically.

    Evidence Inducible Myh11-Cre Tgfbr1 KO with ERK-inhibitor and AT1R-blocker rescue, aortic histology

    PMID:27739498

    Open questions at the time
    • Direct molecular link between ALK5 loss and ERK activation not defined
    • Relationship to Loeys-Dietz aneurysm mechanism unresolved
  10. 2016 High

    Extended ALK5 signaling into immune and angiogenic contexts, mediating GDF-15 suppression of integrin activation in neutrophils and placing ALK5 downstream of Dll4/Notch/Nrp1 in tip-stalk cell specification.

    Evidence Conditional neutrophil ALK5 KO with Rap-1 assays; Nrp1 genetic manipulation with Smad2/3 and sprouting readouts

    PMID:26081042 PMID:27235139

    Open questions at the time
    • Whether these effects are Smad-dependent or Smad-independent not fully resolved
  11. 2019 High

    Identified novel ligands and effectors of ALK5, including direct GDNF binding at His39/Asp76 to activate hepatic stellate cells, and Gadd45b coupling in post-ischemic neurogenesis.

    Evidence SPR, molecular docking, residue mutagenesis and Co-IP for GDNF; lentiviral ALK5 manipulation with Co-IP and Smad2/3 assays for Gadd45b

    PMID:31043581 PMID:31171625

    Open questions at the time
    • Whether GDNF-ALK5 signaling requires TGFBR2 not addressed
    • Structural detail of GDNF-ALK5 interface beyond docking lacking
  12. 2021 High

    Established ALK5 as a mechanoreceptor in endothelium that drives EndMT under disturbed shear stress through an ALK5-Shc pathway promoting atherosclerosis, identifying a non-ligand-driven activation mode.

    Evidence ALK5 depletion, force/flow reconstitution, and endothelial Shc genetic targeting in an atherosclerosis model

    PMID:34244146

    Open questions at the time
    • How mechanical force activates ALK5 biochemically not defined
    • Relationship between mechano-activation and ligand-dependent activation unclear
  13. 2022 High

    Defined post-translational and stress-driven control of ALK5: CYLD loss stabilizes the receptor to enhance invasion, CD147 binds to promote its activation and endocytosis, and mitochondrial dysfunction amplifies ALK5-SMAD2 signaling via MAPKs.

    Evidence CYLD siRNA with stability and invasion assays; CD147 Co-IP and AAV cardiac models with endocytosis readouts; endothelial TFAM/COX10/TRX2 KOs with ALK5 inhibition and SMAD2 rescue

    PMID:29235674 PMID:36496409 PMID:36594096

    Open questions at the time
    • Direct ubiquitination sites on ALK5 not mapped
    • How CD147 binding promotes kinase activation mechanistically unclear
  14. 2023 Medium

    Uncovered epigenetic control of TGFBR1 expression itself, where a TGFβ1-RCN3 feedback loop sequesters EZH2 in the cytoplasm to relieve H3K27me3 repression of the TGFBR1 promoter, sustaining fibrosis.

    Evidence BioID, RCN3-EZH2 Co-IP, H3K27me3 promoter analysis, fibroblast Rcn3 KD bleomycin model

    PMID:37710230

    Open questions at the time
    • Generality of this loop beyond lung fibroblasts unknown
    • Direct EZH2 occupancy dynamics at the TGFBR1 promoter not time-resolved
  15. 2020 Medium

    Linked TGFBR1 loss-of-function to multiple self-healing squamous epithelioma, establishing a digenic inheritance requiring permissive variants at a second 9q locus and distinguishing its mutation spectrum from Loeys-Dietz syndrome.

    Evidence Haplotype and mutation screening across MSSE families with review of co-occurring Loeys-Dietz cases

    PMID:33256177 PMID:9439661

    Open questions at the time
    • Identity of the required second 9q locus not established
    • Mechanistic explanation for tissue-restricted skin phenotype lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALK5's distinct activation modes (ligand binding, mechanical force, GPCR transactivation) and its multiple substrate branches (Smad2/3, Smad1/5, endoglin, Shc) are selected and integrated within a single cell remains unresolved.
  • No structural model integrating substrate selection across conditions
  • Quantitative rules governing canonical vs non-canonical output unknown
  • Crosstalk between mechano- and ligand-driven activation not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
ALK1CD147ENDOGLINGADD45BGDNFSHCSMAD3TGFBR2
Complex memberships
ALK5/ALK1/endoglin/betaglycan complexTGFBR1/TGFBR2 receptor complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 ALK5 (TGFBR1) is required for TGFβ-induced ALK1 signaling in endothelial cells: ALK5 mediates TGFβ-dependent recruitment of ALK1 into a TGFβ receptor complex, and ALK5 kinase activity is required for optimal ALK1 activation. ALK1 in turn directly antagonizes ALK5/Smad2/3 signaling. Endothelial cells lacking ALK5 (genetic KO), reporter assays, Co-IP/complex formation studies, kinase activity assays Molecular cell High 14580334
1999 TGFβ1-induced epithelial-to-mesenchymal transition (EMT) in mammary epithelial cells is mediated specifically by TGFBR1/ALK5 and downstream Smad2/Smad3/Smad4. Constitutively active ALK5 alone at high levels drives full EMT, while low ALK5 activity combined with Smad2+Smad4 or Smad3+Smad4 cooperatively induces EMT. Adenoviral expression of constitutively active ALK5, dominant-negative constructs, Smad co-transfection, actin cytoskeleton reorganization and E-cadherin/β-catenin relocalization as readouts Journal of cell science High 10574705
2004 Palatal fusion driven by TGFβ3 requires ALK5/TGFBR1 signaling through the Smad2-dependent pathway. Activation of ALK5 in Tgf-beta3-null palatal epithelium rescues fusion; inactivation of ALK5 in wild-type prevents fusion. A Smad-signaling-deficient ALK5 mutant (kinase-active but Smad-unable) cannot rescue fusion, establishing that Smad-dependent signaling downstream of ALK5 is required. Conditional genetic rescue (activated/kinase-dead ALK5 in Tgf-beta3 KO), Smad2 phosphorylation assays, palatal explant culture Developmental biology High 14729481
2005 TGFBR1 mutations associated with Loeys-Dietz syndrome (a connective tissue disorder with cardiovascular, craniofacial and skeletal manifestations) paradoxically result in increased TGFβ signaling in patient tissues (elevated collagen, CTGF, and nuclear phospho-Smad2), despite selected mutant alleles being unable to support TGFβ signal propagation in vitro. Patient-derived cells and tissues; immunostaining for phospho-Smad2, collagen, CTGF; TGFβ signaling kinetics assays Nature genetics High 15731757
2005 ALK5 (TGFBR1) and Smad4 are required for TGFβ1-induced endothelial permeability increase and actin stress fiber formation with MLC and MYPT1 phosphorylation. ALK1 is not involved in this pathway. siRNA depletion of ALK5 or Smad4 in endothelial cells, pharmacological ALK5 inhibition (SB431542), permeability assay, immunofluorescence FEBS letters Medium 16004987
2005 The TGFBR1*6A polymorphism (9-bp in-frame deletion in exon 1) is somatically acquired in cancers, and the signal peptide sequence (not the mature receptor) determines its altered signaling. TGFBR1*6A may convert TGFβ growth-inhibitory signals into growth-stimulatory signals in breast and colorectal cancer cells. In vitro translation assays for signal sequence cleavage site determination, stable transfection of MCF-7 cells, TGFβ-dependent proliferation assays JAMA Medium 16204663
2006 ALK5 (TGFBR1) expression in blood vessels is restricted to medial and adventitial layers but is absent from intimal endothelium (where ALK1 predominates). ALK5-null embryos have defects in vascular smooth muscle layer formation but intact vascular lumen formation, in contrast to the severe lumen dilation seen in ALK1-null mice, demonstrating distinct non-overlapping functions. Alk5-lacZ knockin reporter mice, in situ hybridization/lacZ staining, comparison with Alk5-null and Alk1-null phenotypes Laboratory investigation High 16344855
2008 TGFβ-stimulated phosphorylation of Smad1 and Smad5 (canonically associated with BMP signaling) requires the kinase activity AND specifically the L45 loop motif of ALK5/TGFBR1, as shown by shRNA-resistant ALK5 mutants and in vitro kinase assays. This non-canonical Smad1/5 phosphorylation by ALK5 is essential for TGFβ-stimulated cell migration. shRNA-resistant ALK5 L45-loop mutants in ALK5-depleted cells, in vitro kinase assays, Smad1/5 co-depletion studies, migration assays The EMBO journal High 19096363
2008 In human chondrocytes, ALK5 forms complexes with ALK1, TGFBR2, endoglin, and betaglycan. Both ALK1 and ALK5 are required for TGFβ-induced Smad1/5 phosphorylation, while only ALK5 is essential for TGFβ-induced Smad3 phosphorylation. ALK1 inhibits while ALK5 potentiates Smad3-driven transcription and expression of PAI-1, fibronectin, and type II collagen. Affinity labeling/immunoprecipitation, Western blot, promoter/luciferase assays, Smad phosphorylation assays, varying ALK1/ALK5 expression levels Journal of bone and mineral research High 18333754
2008 ALK5/TGFBR1 phosphorylates the endoglin cytoplasmic domain basally at serines 646 and 649. Loss of phosphorylation at S646 abrogates endoglin-mediated inhibition of Smad1/5/8 signaling in response to TGFβ and endothelial cell migration, while loss of both S646 and S649 eliminates endoglin-mediated inhibition of Smad1/5/8 in response to BMP-9. Site-directed mutagenesis of endoglin phosphorylation sites, Smad1/5/8 reporter assays, endothelial migration assays Carcinogenesis High 20042635
2008 Constitutively activated ALK5 (ALK5L193A,P194A,T204D) directed to embryonic myocardium arrests cardiac looping morphogenesis, causes linear/dilated/hypoplastic heart tube, and induces premature expression of the CDK inhibitor p21, establishing an ALK5-sensitive pathway in cardiac morphogenesis and proliferation control. Cardiac-specific transgenic mice with constitutively active ALK5, morphological analysis, p21/Nkx2.5/dHAND expression analysis Developmental biology Medium 9676193
2008 ALK5/TGFBR1 regulates tooth initiation and early mandible patterning through a pathway independent of TGFBR2. Neural crest-specific Alk5 knockout causes defects not seen in Tgfbr2 knockout, including delayed tooth initiation and altered expression of Msx1, Bmp4, Bmp2, Pax9, Alx4, Lhx6/7 and Gsc. ALK5 controls CNC cell survival through Gsc regulation. Conditional knockout (Wnt1-Cre;Alk5fl/fl vs Wnt1-Cre;Tgfbr2fl/fl), comparative phenotypic analysis, gene expression analysis (in situ hybridization, RT-PCR) Developmental biology High 18572160
2009 Tgfbr1 haploinsufficiency reduces Smad2 and Smad3 phosphorylation and increases cyclin D1 expression and cellular proliferation in colonic epithelium, establishing that TGFBR1 acts as a dose-dependent tumor suppressor in the intestine through Smad-mediated growth control. Tgfbr1+/- mice crossed with ApcMin/+ mice; intestinal tumor counting, Smad phosphorylation Western blots, cyclin D1 immunohistochemistry, BrdU proliferation assays Cancer research High 19147584
2009 TGFβ1 and TGFBR1 are expressed in secreting ameloblasts, and activated TGFBR1 specifically promotes MMP20 mRNA expression (but not KLK4) in ameloblast-lineage cells, establishing a TGFβ/TGFBR1→MMP20 axis in amelogenesis. Immunohistochemistry in developing teeth, constitutively active TGFBR1 vector transfection into ALC cells, RT-PCR for MMP20 and KLK4 Anatomical record Medium 19462458
2010 ALK5 signaling in lung epithelium controls Clara cell differentiation. Deletion of Alk5 in embryonic lung epithelium blocks Clara cell differentiation and inhibits Hes1 expression. Mechanistically, ALK5 regulates Hes1 expression by inhibiting Pten, which in turn activates ERK and AKT phosphorylation. Conditional Alk5 KO (Gata5-Cre), lung epithelial cell in vitro experiments, Pten/ERK/AKT pathway analysis, Hes1 expression Development Medium 20147383
2015 Neuropilin-1 (Nrp1) suppresses the stalk-cell phenotype in angiogenesis by limiting Smad2/3 activation through both ALK1 and ALK5. Notch downregulates Nrp1, thereby relieving inhibition of ALK1 and ALK5 to drive stalk-cell behavior, placing ALK5 downstream of the Dll4/Notch/Nrp1 axis in tip-stalk cell specification. Genetic manipulation of Nrp1 in endothelial cells, Smad2/3 phosphorylation assays, angiogenic sprouting assays in vivo and in vitro Nature communications High 26081042
2016 GDF-15 inhibits CXCL1-induced β2-integrin activation and neutrophil recruitment via the ALK5 (TGF-βRI)/TGF-βRII heterodimer. Mechanistically, GDF-15 and TGFβ1 inhibit integrin activation by blocking Rap-1 activation in a CalDAG-GEF1 and Cdc42-dependent manner. Conditional gene inactivation of ALK5 or TGFBR2 in neutrophils; small-molecule inhibitors, antibodies, siRNA; intravital microscopy; β2-integrin activation assays; Rap-1 activity assays Blood High 27235139
2016 Smooth muscle cell-specific deletion of Tgfbr1 in adult mice causes rapid and severe aortic aneurysm (100% penetrance). Loss of TGFBR1 activates TGFBR2-ERK signaling and upregulates angiotensin-converting enzyme; inhibiting ERK phosphorylation or blocking the AngII/AT1R pathway prevents aneurysmal degeneration, placing TGFBR1 upstream of ERK and AngII/AT1R in aortic wall homeostasis. Inducible SMC-specific Cre-loxP knockout (Myh11-Cre), ERK inhibitor treatment, AT1R blocker treatment, aortic histology and molecular analysis Scientific reports High 27739498
2016 ALK5 controls mesodermal progenitor fate in the lung: Alk5 deletion in mesodermal progenitors inhibits αSMA+ myofibroblast differentiation and increases lipofibroblasts. This is mediated through direct and indirect modulation of PDGFRα, PPARγ, PRRX1, and ZFP423 signaling. Conditional Alk5 KO in lung mesoderm, cell lineage analysis, gene expression analysis of downstream pathway components BMC biology Medium 26984772
2017 TGFβ1 stimulates collagen deposition by mesenchymal stromal cells via the ALK5/Smad3 signaling pathway, and ALK5 inhibition with galunisertib ameliorates myelofibrosis in MPL and JAK2 mouse models. ALK5 inhibitor treatment in vitro and in vivo (MPL and JAK2 murine MF models), Smad3 phosphorylation assays, collagen I and III measurement JCI insight Medium 28405618
2018 CYLD deubiquitinase loss promotes ALK5 stabilization (increased protein stability) in oral squamous cell carcinoma, leading to enhanced TGFβ signaling (increased Smad3 phosphorylation) and cell invasion. ALK5 inhibitor completely blocks the invasive phenotype induced by CYLD knockdown. siRNA knockdown of CYLD, ALK5 protein stability assays, Smad3 phosphorylation Western blot, invasion assays, ALK5 inhibitor rescue The Journal of pathology Medium 29235674
2018 Pericyte ALK5 controls brain endothelial morphogenesis through a TIMP3-dependent mechanism: ALK5-depleted pericytes downregulate TIMP3, leading to elevated perivascular MMP activity, endothelial hyperproliferation, reduced pericyte coverage, and germinal matrix hemorrhage. TIMP3 administration rescues endothelial morphogenesis in ALK5 pericyte mutants. Conditional Alk5 KO in pericytes, TIMP3 protein administration rescue, MMP activity assays, histological analysis of brain microvessels Developmental cell High 29456135
2019 ALK5 (TGFBR1) inactivation in the mouse uterus leads to metastatic endometrial adenocarcinoma that is estrogen-dependent and requires prior mating (postpartum context), establishing that TGFβ signaling through TGFBR1/ALK5 in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum repair. Conditional Alk5 KO in uterus (progesterone receptor Cre), histopathology, ERα and PR immunostaining, metastasis analysis PNAS High 30655341
2019 GDNF directly binds ALK5/TGFBR1 at His39 and Asp76 residues to activate hepatic stellate cells via Smad2/3 signaling (not via GFRα1), promoting liver fibrosis. This binding was determined by surface plasmon resonance, molecular docking, mutagenesis, and co-immunoprecipitation. Surface plasmon resonance, molecular docking, mutagenesis of ALK5 binding residues, Co-IP, adenoviral GDNF overexpression/CRISPR silencing in mice, primary HSC activation assays Gut High 31171625
2019 ALK5 signaling mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b. ALK5 regulates Gadd45b protein levels through Smad2/3 phosphorylation, and ALK5 directly co-immunoprecipitates with Gadd45b. Lentiviral ALK5 KD/overexpression in vivo, Smad2/3 phosphorylation assays, co-immunoprecipitation of ALK5 and Gadd45b, axonal/dendritic plasticity assays Cell death & disease Medium 31043581
2020 TP-008, a selective chemical probe for ALK4 and ALK5, potently inhibits ALK5 kinase activity and strongly abrogates phosphorylation of SMAD2 in cells, confirming that ALK5 kinase activity is directly responsible for SMAD2 phosphorylation. Kinase selectivity profiling, cellular SMAD2 phosphorylation assays with TP-008 and matched negative control compound ACS chemical biology Medium 32176847
2021 ALK5 acts as a mechanoreceptor in endothelial cells to drive EndMT in response to disturbed shear stress through an ALK5-Shc signaling pathway, independent of other mechanosensors. Depletion of ALK5 abrogates shear stress-induced EndMT, and genetic targeting of endothelial Shc reduces EndMT and atherosclerosis in areas of disturbed flow. ALK5 depletion in endothelial cells, tensional force and flow reconstitution experiments, endothelial-specific Shc gene targeting in atherosclerosis model, EndMT marker analysis Science advances High 34244146
2021 GDF-8 stimulates trophoblast cell invasion by upregulating MMP2 expression via the ALK5-SMAD2/3 signaling pathway. MMP9 expression is not affected by GDF-8. Knockdown of MMP2 attenuates GDF-8-induced invasiveness. siRNA knockdown of ALK5, SMAD2, SMAD3 in HTR-8/SVneo cells, MMP2/MMP9 expression assays, invasion assays Reproduction Medium 34432647
2022 Simultaneous muscle-specific knockout of Tgfbr1 and Acvr1b (but not either alone) induces substantial myofiber hypertrophy via increased Akt and p70S6K phosphorylation and reduced E3 ligase expression, demonstrating synergistic roles of these two TGFβ type I receptors in regulating muscle fiber size and regeneration. Single and double conditional KO mice (Tgfbr1 and Acvr1b), phospho-Akt/p70S6K Western blots, E3 ligase expression, satellite cell and macrophage quantification, cardiotoxin injury model eLife High 35323108
2022 Mitochondrial dysfunction induces enhanced ALK5-SMAD2 signaling through MAPKs-mediated phosphorylation of SMAD2 with mitochondrial localization of SMAD2, leading to retinal arteriovenous malformations. Pharmacological blockade of ALK5 or genetic SMAD2 deficiency prevents retinal vascular malformations in mitochondrial dysfunction mouse models. Endothelial-specific KO of TFAM, COX10, or TRX2; single-cell RNA-seq; pharmacological ALK5 inhibition; SMAD2 genetic KO rescue; phospho-SMAD2 localization studies Nature communications High 36496409
2022 CD147 directly binds ALK5, promoting ALK5 activation and endocytosis, leading to SMAD2/3 phosphorylation and nuclear translocation. N-glycosylation of CD147 (by GNT-V) under high glucose conditions prevents its ubiquitin-proteasome degradation, sustaining ALK5 activation and cardiac fibrosis in diabetic cardiomyopathy. Co-IP of CD147 and ALK5, AAV9-mediated cardiac-specific CD147 silencing/overexpression, endocytosis assays, SMAD2/3 phosphorylation/nuclear translocation, glycosylation manipulation International journal of biological sciences Medium 36594096
2023 RCN3 promotes fibroblast activation and lung fibrosis through a TGFβ1-RCN3-TGFBR1 positive feedback loop: TGFβ1 upregulates RCN3, which detains EZH2 in the cytoplasm via RCN3-EZH2 interaction, releasing EZH2-H3K27me3 epigenetic repression of TGFBR1 to sustain TGFBR1 expression. BioID protein interaction assay, RCN3-EZH2 Co-IP, epigenetic (H3K27me3) analysis of TGFBR1 promoter, fibroblast-selective Rcn3 KD mouse model, bleomycin fibrosis model Respiratory research Medium 37710230
2023 NRP1 interacts with TGFBR2 through their cytoplasmic domains, activating the TGFBR1/TGFBR2 complex, which facilitates macropinocytosis-mediated KSHV internalization into mesenchymal stem cells via Cdc42 and Rac1. Co-IP of NRP1 and TGFBR2, NRP1 KO and overexpression in MSCs, KSHV infection assays, macropinocytosis assays, Cdc42/Rac1 activity measurements Science advances Medium 37224259
2020 LPAR5 (lysophosphatidic acid receptor 5) transactivates TGFBR1 to stimulate mRNA expression of GAG biosynthesis genes XYLT1 and CHST3 in vascular smooth muscle cells. This LPAR5-to-TGFBR1 transactivation occurs through a ROCK-dependent pathway, and ROS/Akt signaling are not involved. Pharmacological inhibition of LPAR5 and TGFBR1, ROCK inhibitor experiments, XYLT1/CHST3 mRNA expression assays, ROS and Akt pathway analysis in VSMCs Biochimica et biophysica acta. Molecular cell research Medium 32920014
1999 Multiple self-healing squamous epithelioma (MSSE) maps to chromosome 9q22-q31, and genetic mapping excluded XPA and PTCH as causative genes, narrowing the interval. TGFBR1 (also known as MSSE/ESS1 by alias) was later identified as the MSSE gene through loss-of-function mutations. Linkage analysis, haplotype analysis, SSCP, DNA sequencing of candidate genes in MSSE families Human genetics Low 9439661
2020 Loss-of-function mutations in TGFBR1 cause MSSE (Ferguson-Smith disease/multiple self-healing squamous epithelioma) in a digenic manner requiring permissive variants at a second linked locus on chromosome 9q. The spectrum of TGFBR1 mutations in MSSE differs from those in Loeys-Dietz syndrome. Haplotype analysis, mutation screening in MSSE families, review of families with both MSSE and Loeys-Dietz syndrome Genes Medium 33256177
2017 Lumican C-terminal peptide LumC13 binds directly to ALK5/TGFBR1, forming a stable complex. Computational design of LumC13 derivatives identified minimal residues required for stable lumican/ALK5 complex formation, and these peptides promote corneal epithelial cell migration and wound healing. In silico binding modeling, in vitro cell migration assays, in vivo corneal wound healing, computational derivative design with experimental validation Scientific reports Medium 28181591
2021 TGFβ1 induces ZIP8 expression via the ALK5-Smad2/3 signaling pathway in vascular endothelial cells, with Smad3-mediated induction occurring with or without p38 MAPK co-activation. This upregulation of ZIP8 increases intracellular cadmium accumulation and potentiates cadmium cytotoxicity. ALK5 inhibitor (SB431542), Smad2/3 knockdown, p38 MAPK inhibitor, ZIP8 expression assays, cadmium uptake and cytotoxicity assays in endothelial cells International journal of molecular sciences Medium 35008873

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature genetics 1295 15731757
2003 Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Molecular cell 594 14580334
1999 TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. Journal of cell science 365 10574705
2005 The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer science 273 16271073
2007 ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 186 17911384
2008 TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. The EMBO journal 151 19096363
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 138 26081042
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 135 18333754
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 116 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
2019 Circular RNA CircCACTIN Promotes Gastric Cancer Progression by Sponging MiR-331-3p and Regulating TGFBR1 Expression. International journal of biological sciences 90 31182928
2018 Linc00462 promotes pancreatic cancer invasiveness through the miR-665/TGFBR1-TGFBR2/SMAD2/3 pathway. Cell death & disease 87 29899418
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 82 35752078
2006 Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Laboratory investigation; a journal of technical methods and pathology 82 16344855
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
2003 TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 74 12947057
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
2021 Mechanical forces regulate endothelial-to-mesenchymal transition and atherosclerosis via an Alk5-Shc mechanotransduction pathway. Science advances 65 34244146
2006 Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation. Developmental biology 64 17250821
2008 TGF-beta type I receptor Alk5 regulates tooth initiation and mandible patterning in a type II receptor-independent manner. Developmental biology 62 18572160
2016 Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events. Scientific reports 59 27739498
2018 miR-22 regulates C2C12 myoblast proliferation and differentiation by targeting TGFBR1. European journal of cell biology 55 29588073
2009 ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration. Carcinogenesis 54 20042635
2018 Luteolin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting TGFBR1 Signaling. Frontiers in pharmacology 53 30298006
2019 ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b. Cell death & disease 52 31043581
2016 TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial-mesenchymal transition. Experimental & molecular medicine 52 27885255
2009 Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development. Cancer research 49 19147584
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
2019 Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling. Gut 45 31171625
2017 Efficacy of ALK5 inhibition in myelofibrosis. JCI insight 45 28405618
2005 ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial permeability. FEBS letters 45 16004987
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
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
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
2018 Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental cell 39 29456135
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
2019 Let-7f-5p regulates TGFBR1 in glucocorticoid-inhibited osteoblast differentiation and ameliorates glucocorticoid-induced bone loss. International journal of biological sciences 37 31592234
2017 Lumican Peptides: Rational Design Targeting ALK5/TGFBRI. Scientific reports 36 28181591
2021 Taohong siwu decoction attenuates myocardial fibrosis by inhibiting fibrosis proliferation and collagen deposition via TGFBR1 signaling pathway. Journal of ethnopharmacology 35 33460756
2009 TGF-beta1 and TGFBR1 are expressed in ameloblasts and promote MMP20 expression. Anatomical record (Hoboken, N.J. : 2007) 33 19462458
1998 A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. Developmental biology 33 9676193
1997 Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes. Human genetics 32 9439661
2017 Cartilage-specific deletion of Alk5 gene results in a progressive osteoarthritis-like phenotype in mice. Osteoarthritis and cartilage 31 28716756
2018 Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. The Journal of pathology 29 29235674
2016 Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC biology 29 26984772
2011 Tgf-beta type I receptor (Alk5) kinase inhibitors in oncology. Current pharmaceutical biotechnology 29 21619541
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 28 37931653
2015 Activin Receptor-Like Kinase Receptors ALK5 and ALK1 Are Both Required for TGFβ-Induced Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells. PloS one 28 26720610
2006 Inhibition of ALK5 as a new approach to treat liver fibrotic diseases. Drug news & perspectives 28 16628263
2022 FOXP3 activated-LINC01232 accelerates the stemness of non-small cell lung carcinoma by activating TGF-β signaling pathway and recruiting IGF2BP2 to stabilize TGFBR1. Experimental cell research 27 35026283
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
2003 ALK5 inhibition in renal disease. Current opinion in pharmacology 27 12681245
2014 TGFBR1 and cancer susceptibility. Transactions of the American Clinical and Climatological Association 26 25125747
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
2010 ALK5 inhibition blocks TGFß-induced CCN2 expression in gingival fibroblasts. Journal of dental research 25 20924066
2023 Neuropilin 1 is an entry receptor for KSHV infection of mesenchymal stem cell through TGFBR1/2-mediated macropinocytosis. Science advances 24 37224259
2014 TGFBR1 is required for mouse myometrial development. Molecular endocrinology (Baltimore, Md.) 24 24506537
2014 ZNF580 mediates eNOS expression and endothelial cell migration/proliferation via the TGF-β1/ALK5/Smad2 pathway. Molecular and cellular biochemistry 24 24771066
2020 miR-96-5p regulated TGF-β/SMAD signaling pathway and suppressed endometrial cell viability and migration via targeting TGFBR1. Cell cycle (Georgetown, Tex.) 23 32635855
2008 Pharmacokinetics and tissue distribution of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; a novel ALK5 inhibitor and a potential anti-fibrosis drug. Xenobiotica; the fate of foreign compounds in biological systems 23 18274960
2023 TGFβ1-RCN3-TGFBR1 loop facilitates pulmonary fibrosis by orchestrating fibroblast activation. Respiratory research 22 37710230
2022 GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β-catenin and ALK5/SMAD2/3 pathways. Cell proliferation 22 35920128
2017 Serelaxin inhibits differentiation and fibrotic behaviors of cardiac fibroblasts by suppressing ALK-5/Smad2/3 signaling pathway. Experimental cell research 22 28987540
2001 The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. The Journal of pathology 22 11329144
2016 Galangin inhibits hypertrophic scar formation via ALK5/Smad2/3 signaling pathway. Molecular and cellular biochemistry 21 26728998
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
2012 Association between TGFBR1 polymorphisms and cancer risk: a meta-analysis of 35 case-control studies. PloS one 19 22905183
2022 Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors. Medicinal chemistry (Shariqah (United Arab Emirates)) 18 34182915
2022 Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration. eLife 18 35323108
2022 Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature communications 18 36496409
2019 MiR-27 alleviates myocardial cell damage induced by hypoxia/reoxygenation via targeting TGFBR1 and inhibiting NF-κB pathway. The Kaohsiung journal of medical sciences 18 31169351
2017 Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. Journal of vascular surgery 18 28847661
2010 Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs. Journal of experimental & clinical cancer research : CR 18 20500843
2023 N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation. International journal of biological sciences 17 36594096
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
2017 Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors. Bioorganic & medicinal chemistry letters 17 28359790
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
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 GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression. Reproduction (Cambridge, England) 16 34432647
2020 Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3. Biochimica et biophysica acta. Molecular cell research 16 32920014
2006 The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity. Oncogene 16 16170343
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
2020 Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p. Communications biology 15 32581266
2018 Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors. Pulmonary pharmacology & therapeutics 15 30448291
2011 Differential signalling through ALK-1 and ALK-5 regulates leptin expression in mesenchymal stem cells. Stem cells and development 15 22087763
2006 ALK-5 mediates endogenous and TGF-beta1-induced expression of connective tissue growth factor in embryonic lung. American journal of respiratory cell and molecular biology 15 17197570
2020 Multiple Self-Healing Squamous Epithelioma (MSSE): A Digenic Trait Associated with Loss of Function Mutations in TGFBR1 and Variants at a Second Linked Locus on the Long Arm of Chromosome 9. Genes 14 33256177
2009 TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk. British journal of cancer 14 19401691

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