Affinage

ACVR1B

Activin receptor type-1B · UniProt P36896

Length
505 aa
Mass
56.8 kDa
Annotated
2026-04-28
75 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACVR1B (ALK4) is a type I serine/threonine kinase receptor of the TGF-β superfamily that transduces activin, Nodal, and related ligand signals primarily through SMAD2/3-SMAD4 phosphorylation, governing embryonic patterning, tissue homeostasis, and cell fate decisions across diverse lineages. ALK4 forms heteromeric complexes with type II receptors (ActRII/ActRIIB) and engages ligands through a hydrophobic interface on its extracellular domain (Leu40, Ile70, Val73, Leu75, Pro77), while the co-receptor Cripto-1 bridges Nodal to ALK4 via its CFC domain to enable non-canonical ligand recruitment (PMID:12665502, PMID:39840816, PMID:11909953). ALK4 is essential for gastrulation, left-right axis determination, hair follicle cycling, somatostatin interneuron specification, adipocyte precursor maintenance, and muscle mass regulation, and it functions as a tumor suppressor in the pancreas where its loss cooperates with oncogenic KRAS to accelerate neoplasia (PMID:9512518, PMID:21191412, PMID:31676717, PMID:36403856, PMID:35323108, PMID:39111635). Beyond canonical SMAD signaling, ALK4 operates through SMAD-independent pathways in neuronal differentiation and cooperates with dopamine D1 receptor signaling to regulate ΔFosB alternative splicing via PCBP1-Smad3 nuclear translocation in striatal neurons (PMID:20226172, PMID:35730718).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Constitutively active ALK4 was shown to induce dorso-anterior mesoderm and endoderm in Xenopus, establishing that ALK4 signals in a pathway distinct from ALK2 and mediates activin-like dorsal patterning.

    Evidence Constitutively active/dominant-negative receptor injection in Xenopus animal caps with dose-response gene expression readouts

    PMID:9367435

    Open questions at the time
    • Endogenous ligand identity not resolved
    • Downstream transcriptional targets not identified
    • Mechanism of ALK2 antagonism unclear
  2. 1998 High

    Genetic knockout demonstrated that ALK4 is indispensable for gastrulation: null embryos arrest before primitive streak formation, and chimera analysis established that ALK4 functions cell-autonomously in both epiblast and extraembryonic ectoderm.

    Evidence Gene targeting (knockout) and chimera analysis in mice with embryo histology

    PMID:9512518

    Open questions at the time
    • Specific ligand(s) acting through ALK4 in vivo not identified
    • Downstream signaling pathway in gastrulation not characterized
  3. 1999 Medium

    Domain-swap experiments identified a 7-amino-acid loop between kinase subdomains IV and V as the structural determinant of ALK4's dorsal mesoderm-inducing specificity, distinguishing it from ALK2.

    Evidence Chimeric ALK4/ALK2 receptor construction with Xenopus animal cap assays

    PMID:10075688

    Open questions at the time
    • Crystal structure of kinase domain not available
    • Specific SMAD or non-SMAD effectors engaged by this loop not determined
  4. 2000 High

    Truncated ALK4 isoforms found in pituitary tumors were shown to act as dominant-negative receptors that complex with type II receptors but cannot be phosphorylated, blocking activin's antiproliferative effect — the first evidence for ALK4 loss-of-function in human neoplasia.

    Evidence Co-immunoprecipitation, reporter assay, and growth inhibition assay in stably transfected cells

    PMID:11117535

    Open questions at the time
    • Prevalence of truncated isoforms across tumor types unknown
    • In vivo tumor-promoting role not demonstrated
  5. 2001 High

    Two concurrent advances defined ALK4 as the obligate type I receptor for Nodal signaling and identified somatic ACVR1B mutations in pancreatic cancer, establishing its dual role in developmental signaling and tumor suppression.

    Evidence Receptor reconstitution and dominant-negative assays in Xenopus embryos with co-IP (Nodal); direct sequencing of pancreatic cancer specimens (mutations)

    PMID:11248065 PMID:11485994

    Open questions at the time
    • Cripto-ALK4 binding interface not structurally resolved
    • Functional consequence of specific pancreatic cancer mutations not tested
  6. 2002 High

    SB-431542 was characterized as a selective inhibitor of ALK4/ALK5/ALK7 kinase activity, providing a pharmacological tool that discriminates activin/TGF-β signaling from BMP and MAPK pathways, and Cripto-1 was shown to directly bind ALK4 on mammalian cell surfaces to enable Nodal-dependent SMAD2 phosphorylation.

    Evidence In vitro kinase inhibition assays with selectivity panel; FACS binding, co-IP, and SMAD2 phosphorylation assay for Cripto-ALK4 interaction

    PMID:11909953 PMID:12065756

    Open questions at the time
    • Co-crystal structure of inhibitor-ALK4 not available
    • Cripto binding site on ALK4 not mapped at residue level
  7. 2003 High

    Mutagenesis of the ALK4 extracellular domain identified five hydrophobic residues (Leu40, Ile70, Val73, Leu75, Pro77) as the activin-binding surface, providing the first residue-level map of ligand-receptor contact.

    Evidence Extracellular domain mutagenesis with 125I-activin cross-linking and dominant-negative activity assay

    PMID:12665502

    Open questions at the time
    • Crystal structure of the ternary activin-ActRII-ALK4 complex not solved
    • Whether these residues also contact Nodal or other ligands not tested
  8. 2004 High

    Activin's fingertip/wrist region was shown to contact ALK4 directly via an M108A mutant that retains type II receptor binding but loses ALK4 recruitment, and ALK4 was demonstrated to participate in left-right axis determination in Xenopus through signaling downstream of multiple Nodal-related ligands.

    Evidence Site-directed mutagenesis with cross-linking (activin-ALK4); co-IP from embryo homogenates with dominant-negative/constitutively active receptor injection for L-R axis

    PMID:15063168 PMID:15123686

    Open questions at the time
    • Left-right phenotype not validated in mammalian models
    • Structural basis of M108A disruption not determined at atomic level
  9. 2007 High

    miR-24 was identified as a post-transcriptional regulator of ALK4, demonstrating that ALK4 protein levels and consequently activin-SMAD2 signaling in erythroid differentiation are subject to microRNA control.

    Evidence 3'-UTR luciferase reporter assay, ectopic miR-24 expression, erythroid colony assay in K562 and CD34+ cells

    PMID:17906079

    Open questions at the time
    • Physiological relevance during normal hematopoiesis not established
    • Whether other miRNAs cooperate in ALK4 regulation not explored
  10. 2009 Medium

    NMR and SPR analyses structurally characterized the Cripto CFC domain–ALK4 interaction, identifying exposed residues H120 and W124 on Cripto as key contact points, confirming the direct and specific nature of the co-receptor–receptor interaction.

    Evidence NMR structure of CFC domain, SPR binding kinetics, molecular docking

    PMID:19035567

    Open questions at the time
    • Co-crystal structure of CFC-ALK4 complex not obtained
    • Affinity measured in µM range — physiological relevance of weak interaction debated
  11. 2010 High

    Conditional epithelial-specific deletion of Acvr1b revealed a cell-autonomous requirement for ALK4 in hair follicle cycling; separately, ALK4 was found to promote neuronal differentiation via a SMAD-independent mechanism in neuroblastoma cells.

    Evidence K14-Cre conditional KO in mice with histological phenotyping (hair follicle); siRNA knockdown, ChIP, and neurite outgrowth assay in SK-N-SH cells (SMAD-independent)

    PMID:20226172 PMID:21191412

    Open questions at the time
    • Identity of SMAD-independent downstream effectors not determined
    • Hair follicle phenotype mechanism (which SMAD, which target genes) not resolved
  12. 2015 High

    The full activin A→ALK4→SMAD2/3→SMAD4→SNAIL→MMP2 signaling cascade was delineated in trophoblast invasion, providing a complete pathway from receptor to effector protease.

    Evidence Sequential siRNA knockdown of ALK4, SMAD2/3, SMAD4, SNAIL each abolished activin-induced MMP2 and invasion in Matrigel assay

    PMID:26305619

    Open questions at the time
    • Whether this cascade operates in vivo during implantation not tested
    • Contribution of other type I receptors (ALK7) not excluded
  13. 2020 High

    Multiple studies expanded ALK4's tissue-specific roles: ALK4 mediates activin A-induced integrin β1 upregulation in trophoblasts, white matter remyelination via oligodendrocyte maturation after ischemic stroke, cadmium-induced renal cell death via Smad3/Akt, and somatostatin interneuron specification through Smad2-SATB1 interaction at the somatostatin promoter.

    Evidence siRNA/shRNA knockdown and conditional KO with invasion assays, MCAO/R mouse model, cell viability assays, and ChIP respectively

    PMID:30804470 PMID:31676717 PMID:33230889 PMID:33345977

    Open questions at the time
    • Whether oligodendrocyte remyelination role is ALK4-specific or shared with ALK5/ALK7 not resolved
    • In vivo validation of cadmium toxicity pathway lacking
  14. 2022 High

    Three distinct functional arenas for ALK4 were established: cooperation with D1 receptor signaling to regulate ΔFosB splicing in striatal neurons via PCBP1-Smad3; redundancy with TGF-βRI (ALK5) in suppressing muscle hypertrophy; and suppression of adipocyte differentiation via CEBPα/PPARγ repression in precursor cells.

    Evidence Conditional KO in MSNs with behavioral assays; double Tgfbr1/Acvr1b muscle-specific KO with Akt/p70S6K signaling; adipocyte precursor conditional KO with CEBPα rescue

    PMID:35323108 PMID:35730718 PMID:36403856

    Open questions at the time
    • PCBP1-Smad3 splicing mechanism not reconstituted in vitro
    • Whether ALK4 and ALK5 engage identical SMAD complexes in muscle not determined
    • Upstream activin ligand identity in adipose tissue not confirmed
  15. 2024 High

    Cell-type-specific conditional knockout combined with oncogenic Kras formally established ACVR1B as a pancreatic tumor suppressor: Acvr1b loss accelerated precancerous lesion formation from both acinar and ductal cells, resolving two decades of correlative evidence from sequencing studies.

    Evidence Ptf1aCreER and Sox9CreER conditional KO with KrasLSL-G12D, MRI, and histopathology in mice

    PMID:39111635

    Open questions at the time
    • Mechanism by which ALK4 loss cooperates with KRAS not molecularly defined
    • Whether SMAD2 or SMAD3 mediates the tumor-suppressive arm not resolved
  16. 2025 High

    Structural modeling and SPR confirmed that Cripto-1 uses distinct domains to simultaneously bind Nodal and ALK4, forming a ternary bridge complex unique among TGF-β family signaling modes; separately, ALK4 loss was found to enhance canonical TGF-β signaling by upregulating MGAT5/galectin-3-mediated glycosylation that stabilizes TGF-β receptors at the cell surface.

    Evidence AlphaFold3 modeling validated by SPR and functional SMAD assays (Cripto); MGAT5/galectin-3 depletion and glycosylation inhibition in breast/pancreatic cancer models (TGF-β crosstalk)

    PMID:39840816 PMID:41408046

    Open questions at the time
    • Experimental co-crystal structure of Cripto-Nodal-ALK4-ActRIIB quaternary complex not yet solved
    • Whether MGAT5-mediated TGF-β receptor stabilization drives tumor progression in patient tumors not confirmed
    • Therapeutic potential of targeting MGAT5 in ACVR1B-mutant cancers not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full atomic structure of the activin/Nodal–type II receptor–ALK4–Cripto signaling complex, the identity of SMAD-independent effectors in neurons, the mechanism by which ALK4 loss cooperates with oncogenic KRAS in pancreatic tumorigenesis, and whether ALK4's diverse tissue-specific roles use shared or distinct downstream transcriptional programs.
  • No experimental co-crystal structure of the full signaling complex
  • SMAD-independent neuronal effectors unidentified
  • Transcriptional program specificity across tissues not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
ACVR2AACVR2BPCBP1SMAD2SMAD3SMAD4TDGF1TGFBR1
Complex memberships
Activin-ActRII/ActRIIB-ALK4 receptor complexNodal-Cripto-ALK4-ActRIIB signaling complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SB-431542 selectively inhibits ALK4 (ACVR1B), ALK5, and ALK7 kinase activity but not other ALK family members (ALK1, ALK2, ALK3, ALK6), blocking activin and TGF-β signaling without affecting BMP, ERK, JNK, or p38 MAPK pathways. In vitro kinase inhibition assays, cell-based reporter assays, signaling pathway analysis Molecular pharmacology High 12065756
2001 ALK4 (ACVR1B) acts as a type I receptor for Nodal signaling in collaboration with ActRIIB; both receptors can independently bind Xnr1, and Cripto interacts directly with both Xnr1 and ALK4 to enhance Nodal responsiveness. A dominant-negative ALK4 blocks all mesoderm-inducing ligands including Nodal, Xnr1, Xnr2, Xnr4, and Activin. Receptor reconstitution experiments, dominant-negative/constitutively active receptor assays in Xenopus embryos, co-immunoprecipitation Genes & development High 11485994
1998 ActRIB (ACVR1B) is required for egg cylinder organization and gastrulation in mice; ActRIB-/- embryos show disorganized epiblast and extraembryonic ectoderm and arrest before gastrulation. Chimera analysis revealed ActRIB functions in both epiblast and extraembryonic cells to mediate signals required for primitive streak formation. Gene targeting (knockout), chimera analysis, embryo histology Genes & development High 9512518
2001 ACVR1B harbors novel somatic mutations in pancreatic carcinoma, establishing it as a mutated tumor-suppressor gene in this cancer type. Direct sequencing of pancreatic cancer specimens, gene structure characterization Proceedings of the National Academy of Sciences of the United States of America Medium 11248065
2002 Cripto-1 binds directly to ALK4 on mammalian epithelial cell surfaces (shown by FACS and co-immunoprecipitation), and Cripto-1 can phosphorylate Smad2 only in the presence of both Nodal and ALK4, establishing Cripto-1 as a co-receptor that bridges Nodal to ALK4 for Smad signaling. Phage display library screening, co-immunoprecipitation, FACS binding, Smad2 phosphorylation assay Molecular and cellular biology High 11909953
2004 SB-505124 selectively inhibits ALK4, ALK5, and ALK7 kinase activity, blocking downstream Smad2/3 phosphorylation and TGF-β-induced MAPK activation without affecting ALK1, ALK2, ALK3, or ALK6 signaling; it is 3-5x more potent than SB-431542. In vitro kinase assays, Smad2/3 reporter assays, cell-based signaling pathway analysis Molecular pharmacology High 14978253
2004 An activin-A mutant (M108A) retains wild-type affinity for ActRII but cannot form a cross-linked complex with ALK4, demonstrating that the fingertip/wrist region of activin contacts ALK4 directly and identifying M108A as a type II receptor antagonist that blocks activin and myostatin but not TGF-β signaling. Site-directed mutagenesis, cross-linking assays with 125I-activin-A, cell-based signaling assays The Journal of biological chemistry High 15123686
2003 Five hydrophobic residues on the ALK4 extracellular domain (Leu40, Ile70, Val73, Leu75, Pro77) constitute the activin-binding surface; mutation of these residues to alanine substantially reduces ALK4-trunc dominant-negative activity and activin-A cross-linking in the presence of ActRII. Extracellular domain mutagenesis, dominant-negative activity assay, 125I-activin cross-linking The Journal of biological chemistry High 12665502
2000 Truncated ALK4 isoforms (Alk4-2, 4-3, 4-4) expressed in human pituitary tumors function as dominant-negative receptors: they form complexes with type II activin receptors (shown by co-immunoprecipitation) but are not phosphorylated, blocking activin-induced transcription and the antiproliferative effect of activin. Co-immunoprecipitation, reporter assay, stable transfection with growth inhibition assay Molecular endocrinology High 11117535
1997 Constitutively active ALK4 (ALK4*) induces dose-dependent dorso-anterior mesodermal and endodermal markers in Xenopus animal caps, including a secondary axis when injected ventrally, while constitutively active ALK2 (ALK2*) induces only ventral mesodermal markers and antagonizes ALK4* signaling, revealing distinct and interfering signaling pathways for the two activin type I receptors. Constitutively active and dominant-negative receptor injection in Xenopus embryos, animal cap assay, gene expression analysis Development (Cambridge, England) High 9367435
1999 The loop between kinase subdomains IV and V (7 amino acids) in ALK4 mediates its strong dorsal gene-inducing specificity; transferring this loop from ALK4* to ALK2* enables the chimeric receptor to induce dorsal-specific gene expression in Xenopus. Chimeric receptor construction, Xenopus animal cap and embryo assay, gene expression analysis The Journal of biological chemistry Medium 10075688
2007 miR-24 targets the 3'-UTR of ALK4 (ACVR1B) mRNA to reduce ALK4 protein levels, thereby interfering with activin-induced Smad2 phosphorylation and inhibiting erythroid differentiation in K562 cells and CD34+ hematopoietic progenitors. Reporter assay (3'-UTR luciferase), Western blot, ectopic miR-24 expression, erythroid colony assay Blood High 17906079
2009 miR-210 directly targets the AcvR1b (ALK4) 3'-UTR (validated by reporter assay), and its overexpression promotes BMP-4-induced osteoblastic differentiation of ST2 stromal cells by suppressing TGF-β/activin signaling through ALK4 inhibition. Reporter assay, sense/antisense miR-210 transfection, SB431542 pharmacological inhibition, osteoblastic differentiation assay FEBS letters Medium 19520079
2006 ALK4 mediates activin A and B signaling to stimulate FSHβ transcription in gonadotrope cells via Smad3 phosphorylation; ALK7 selectively potentiates activin B (but not activin A) effects on Fshb promoter activity, and both constitutively active ALK4 and ALK7 stimulate Smad2/3 phosphorylation. RT-PCR, transfection of wild-type, kinase-dead, and constitutively active receptor constructs, reporter assay, Western blot, shRNA depletion Reproductive biology and endocrinology Medium 17040568
2004 ALK4 co-immunoprecipitates with multiple TGF-β ligands (AVg Activin-Vg1 chimera, Xnr1, derriere, and endogenous Vg1) in Xenopus embryo homogenates, and constitutively active ALK4 expressed on the right side causes left-right organ reversals; dominant-negative ALK4 on the left side also disrupts organ situs, establishing a left-side requirement for ALK4 signaling in LR axis determination. Co-immunoprecipitation from embryo homogenates, dominant-negative and constitutively active receptor microinjection in Xenopus, Pitx2 expression analysis Developmental biology Medium 15063168
2010 Conditional epithelial-specific deletion of Acvr1b (K14-Cre) in mice causes disruption of hair follicle cycling and severe progressive hair loss, and persistent proliferation of skin epithelial cells, establishing a cell-autonomous role for ACVR1B in hair follicle development and cycling. Conditional knockout mouse (Cre-lox), histological analysis, postnatal phenotype characterization The Journal of investigative dermatology High 21191412
2015 Activin A induces human trophoblast cell invasion through ALK4-SMAD2/3-SMAD4 signaling, which upregulates SNAIL and subsequently MMP2; siRNA knockdown of ALK4, SMAD2/3, SMAD4, or SNAIL each abolished activin A-induced MMP2 expression and invasion. siRNA knockdown, Western blot, Matrigel-coated transwell invasion assay, pharmacological inhibition (SB431542) The Journal of clinical endocrinology and metabolism High 26305619
2013 Pharmacological inhibition of ALK4 and ALK7 (with SB431542) in fetal mouse gonads reveals that Activin/NODAL receptors ALK4 and ALK7 are required for promoting differentiation of male germ cells and their entry into mitotic arrest, while ALK4/5/7 signaling is required for testis cord formation during sex determination. FACS-purified gonadal cells, SB431542 pharmacological inhibition ex vivo, histological and gene expression analysis PloS one Medium 23342175
2009 The Cripto CFC domain interacts directly with ALK4 extracellular domain (Kd in μM range by SPR); NMR structural analysis shows residues H120 and W124 are externally exposed and molecular docking identifies the protein-protein interface consistent with prior mutagenesis, with no binding detected to ActRIIB. NMR structural analysis, surface plasmon resonance binding, molecular docking, synthetic CFC domain peptide Journal of peptide science Medium 19035567
2010 Activin A induces neuronal differentiation and survival in SK-N-SH neuroblastoma cells through ALK4 via a SMAD-independent mechanism: ALK4 activation does not induce SMAD2/3 phosphorylation, SMAD2/3-SMAD4 interaction, nuclear SMAD2/3 accumulation, or SMAD2/3 promoter binding, yet activates TGF-β target genes and promotes neurite outgrowth. siRNA knockdown, Western blot, co-immunoprecipitation, ChIP, neurite outgrowth assay Biochemical and biophysical research communications Medium 20226172
2017 Activin A/ALK4 signaling activates Smad2/3 in atrial fibroblasts to drive atrial fibrosis; ALK4-haplodeficient mice show reduced atrial fibroblast activation, reduced atrial fibrosis, and reduced atrial fibrillation vulnerability after angiotensin II stimulation. ALK4 haplodeficient knockout mice, Ang-II stimulation model, electrophysiological studies, histology, Western blot Basic research in cardiology Medium 28639003
2020 Activin A increases integrin β1 expression in human trophoblasts through ALK4-SMAD2/3-SMAD4 signaling; knockdown of ALK4 or SMAD4 abolishes activin A-induced integrin β1 upregulation, and integrin β1 knockdown reduces activin A-stimulated invasion. siRNA knockdown, Western blot, Matrigel invasion assay, SB431542 pharmacological inhibition FASEB journal Medium 33230889
2022 ALK4 (ACVR1B) cooperates with dopamine D1 receptor signaling to regulate FosB alternative splicing in nucleus accumbens medium spiny neurons: concurrent D1 and ALK4 activation induces PCBP1 interaction with Smad3, nuclear translocation, and binding to FosB exon-4/intron-4 sequences to generate ΔFosB mRNA; ALK4 ablation in MSNs impairs ΔFosB induction and cocaine behavioral sensitization. Co-immunoprecipitation, nuclear translocation assay, conditional ALK4 KO in MSNs, behavioral sensitization assay, RNA binding protein analysis The EMBO journal High 35730718
2022 Simultaneous muscle-specific knockout of Tgfbr1 and Acvr1b in mice induces substantial myofibre hypertrophy via increased Akt and p70S6K phosphorylation and reduced E3 ligase expression; combined knockout also increases satellite cell numbers and improves regeneration after cardiotoxin injury, while single receptor knockouts do not produce these effects. Double conditional knockout mouse, histology, Western blot (Akt/p70S6K phosphorylation), cardiotoxin injury model, gene expression analysis eLife High 35323108
2021 ActRIIB:ALK4-Fc, a heterodimeric fusion of ALK4 and ActRIIB extracellular domains, has a distinct ligand-binding profile compared to ActRIIB-Fc homodimer: it sequesters ActRIIB ligands that inhibit muscle growth but does not trap BMP9 (shown by SPR), improving muscle mass, function, and neuromuscular junction abnormalities in murine DMD, ALS, and disuse atrophy models. Surface plasmon resonance, retinal explant vascular assay, murine disease models, muscle mass/function measurements The Journal of clinical investigation High 33586684
2020 ALK4 signaling in oligodendrocytes mediates Activin A-induced white matter remyelination after ischemic stroke; AAV-based ACVR1B shRNA (with Olig2 promoter) reversed rmActivin A-induced increases in mature oligodendrocyte number, myelin protein levels, and neurological function recovery in MCAO/R mice. AAV-shRNA oligodendrocyte-specific knockdown, MCAO/R mouse model, immunohistochemistry, Western blot, neurological scoring Experimental neurology Medium 33345977
2020 ALK4 (ACVR1B) signaling promotes cadmium-induced death of renal proximal tubular cells via Smad3 phosphorylation and Akt pathway activation; siRNA knockdown of ALK4 or Smad3, or Smad3 inhibitor SIS3, attenuated cadmium-induced cell death. siRNA knockdown, pharmacological inhibition (SB431542, SB505124, SIS3), Western blot, cell viability assay Cell death and differentiation Medium 30804470
2016 ALK4 mediates activin A-stimulated aromatase (P450arom) expression and estradiol secretion in endometrial stromal cells via the ALK4-Smad pathway; pretreatment with ALK4 inhibitor or Smad4 siRNA partially abrogated these effects. Pharmacological inhibition (SB431542), Smad4 siRNA, RT-PCR, ELISA BioMed research international Low 27833918
2019 ALK4-SMAD2/3-SMAD4 signaling mediates activin A-induced suppression of PTX3 in human granulosa-lutein cells; siRNA knockdown of ALK4, SMAD2, SMAD3, or SMAD4 each reversed activin A-induced PTX3 suppression, and ChIP analysis showed phosphorylated SMADs bind to the PTX3 promoter. siRNA knockdown, Western blot, RT-qPCR, ChIP assay, pharmacological inhibition (SB431542) Molecular and cellular endocrinology High 31185247
2020 ALK4-SMAD3-SMAD4 (but not SMAD2) mediates activin A-induced reduction in betaglycan shedding in endometriotic cells; this pathway is distinct from SMAD2 and involves ALK4-dependent suppression of soluble betaglycan release, as shown by ALK4 siRNA and the SMAD3 inhibitor SIS3. siRNA knockdown, SMAD3 inhibitor (SIS3), ELISA, RT-qPCR, Western blot Biomolecules Medium 36551177
2022 ALK4 is preferentially expressed in adipocyte precursors where it suppresses differentiation by repressing CEBPα and PPARγ expression, promoting proliferation and adipose tissue expansion; ALK4 deletion induces premature adipocyte differentiation rescued by CEBPα knockdown. Conditional knockout, CEBPα/PPARγ expression analysis, CEBPα knockdown rescue, adipocyte differentiation assay The Journal of biological chemistry Medium 36403856
2020 ALK4 signaling in cortical somatostatin interneurons regulates their specification: activin-mediated ALK4 signaling induces Smad2 interaction with transcription factor SATB1 and promotes SATB1 nuclear translocation and repositioning at the somatostatin gene promoter; mice lacking ALK4 in GABAergic MGE neurons show deficits in somatostatin interneuron subpopulations. Conditional knockout (GABAergic neuron-specific), co-immunoprecipitation (Smad2-SATB1), nuclear translocation assay, ChIP (SATB1 at somatostatin promoter), immunohistochemistry The Journal of cell biology High 31676717
2022 Activin A promotes integrin β3 expression in human trophoblasts via ALK4-SMAD4 signaling; knockdown of ALK4 or SMAD4 abolished activin A-induced integrin β3 upregulation, and integrin β3 knockdown reduced activin A-promoted invasion. siRNA knockdown, Western blot, RT-PCR, Matrigel invasion assay, SB431542 inhibition Placenta Medium 36244196
2025 Cripto-1 acts as a molecular bridge connecting Nodal (bound to type II receptor ActRIIB) to type I receptor ALK4, forming a unique ternary complex for SMAD2/3 activation; AlphaFold3 modeling, SPR-based interaction analysis, domain-specific antibodies, and functional studies in NTERA-2 cells confirmed that Cripto-1 uses distinct structural domains to bind Nodal and ALK4 separately, contrasting with canonical TGF-β signaling. AlphaFold3 structural modeling, surface plasmon resonance, domain-specific anti-Cripto-1 antibodies, functional SMAD2/3 activation assay Protein science High 39840816
2025 ALK4 loss enhances canonical TGF-β signaling by upregulating MGAT5 and galectin-3, which stabilize TGF-β receptors at the cell surface through β1,6 N-acetylglucosaminyltransferase V-mediated N-linked glycosylation; depleting MGAT5 or inhibiting N-glycosylation suppresses ALK4-loss-induced TGF-β signaling and cancer progression in breast and pancreatic cancer models. In vitro migration/invasion assays, in vivo cancer models, glycosylation analysis, MGAT5/galectin-3 depletion, receptor surface stability assay Nature communications High 41408046
2021 A missense variant p.M345I in ACVR1B reduces transactivation of NODAL-responsive reporters (AR3-Luc, CAGA12-Luc, SBE4-Luc) and decreases SMAD2/3 phosphorylation, indicating the mutation impairs ACVR1B kinase signaling function and is associated with congenital heart disease. Reporter assay, Western blot (SMAD2/3 phosphorylation), 3D protein modeling Experimental cell research Low 34666056
2024 Loss of Acvr1b in the presence of oncogenic Kras accelerates formation of pancreatic intraepithelial neoplasia and IPMN-like precancerous lesions from both acinar and ductal cells, establishing ACVR1B as a tumor suppressor in pancreatic exocrine cells; the effect is context-dependent on cell of origin. Cell-type-specific conditional knockout (Ptf1aCreER or Sox9CreER combined with Acvr1b flox/flox and KrasLSL-G12D), MRI, immunohistochemistry, histopathology Cellular and molecular gastroenterology and hepatology High 39111635
2025 In a mouse model of SLE-associated pulmonary hypertension, Activin A signals via ALK4 in Th17 cells to induce IL-17 secretion, and ALK4 activation in pulmonary microvascular endothelial cells induces endothelial-mesenchymal transition via CTGF upregulation dependent on synergistic pSmad2 and pSTAT3 increases; ALK4 overexpression in Th17 cells worsens SLE-PH in mice while CD4+ T cell depletion alleviates it. CyTOF, Th17-PMEC co-culture, ALK4 overexpression, mouse SLE-PH model, CD4+ T cell depletion, ALK4 inhibitor (vactosertib/TEW-7197), Western blot Arthritis & rheumatology Medium 40395196

Source papers

Stage 0 corpus · 75 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
2004 SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Molecular pharmacology 350 14978253
2002 Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer research 337 12097290
2001 The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes & development 261 11485994
2009 miR-210 promotes osteoblastic differentiation through inhibition of AcvR1b. FEBS letters 187 19520079
1998 The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes & development 184 9512518
2007 MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 173 17906079
2002 Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Molecular and cellular biology 123 11909953
2001 ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proceedings of the National Academy of Sciences of the United States of America 118 11248065
2003 A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src. Cancer research 93 12649175
1997 The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds. Development (Cambridge, England) 77 9367435
2019 Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell death and differentiation 75 30804470
2013 Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PloS one 71 23342175
2017 The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation. Basic research in cardiology 70 28639003
2015 Activin A Increases Human Trophoblast Invasion by Inducing SNAIL-Mediated MMP2 Up-Regulation Through ALK4. The Journal of clinical endocrinology and metabolism 65 26305619
2006 Activin B can signal through both ALK4 and ALK7 in gonadotrope cells. Reproductive biology and endocrinology : RB&E 62 17040568
2004 An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors. The Journal of biological chemistry 59 15123686
2010 Conditional activin receptor type 1B (Acvr1b) knockout mice reveal hair loss abnormality. The Journal of investigative dermatology 47 21191412
2000 Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling. Molecular endocrinology (Baltimore, Md.) 46 11117535
2003 Identification of a functional binding site for activin on the type I receptor ALK4. The Journal of biological chemistry 44 12665502
2006 Activation and roles of ALK4/ALK7-mediated maternal TGFbeta signals in zebrafish embryo. Biochemical and biophysical research communications 38 16696945
2010 Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene. European journal of human genetics : EJHG 36 21063444
2020 Activin A improves the neurological outcome after ischemic stroke in mice by promoting oligodendroglial ACVR1B-mediated white matter remyelination. Experimental neurology 32 33345977
2015 Late Alk4/5/7 signaling is required for anterior skeletal patterning in sea urchin embryos. Development (Cambridge, England) 29 25633352
2004 ALK4 functions as a receptor for multiple TGF beta-related ligands to regulate left-right axis determination and mesoderm induction in Xenopus. Developmental biology 28 15063168
2020 Activin A increases human trophoblast invasion by upregulating integrin β1 through ALK4. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 33230889
2010 Activin A induces neuronal differentiation and survival via ALK4 in a SMAD-independent manner in a subpopulation of human neuroblastomas. Biochemical and biophysical research communications 27 20226172
2021 ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders. The Journal of clinical investigation 26 33586684
2016 New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 27733450
2002 Overexpression of wild-type activin receptor alk4-1 restores activin antiproliferative effects in human pituitary tumor cells. The Journal of clinical endocrinology and metabolism 23 12364468
2016 ACVR1B rs2854464 Is Associated with Sprint/Power Athletic Status in a Large Cohort of Europeans but Not Brazilians. PloS one 22 27253421
2020 A Highly Selective Chemical Probe for Activin Receptor-like Kinases ALK4 and ALK5. ACS chemical biology 19 32176847
2017 Overexpression of ALK4 inhibits cell proliferation and migration through the inactivation of JAK/STAT3 signaling pathway in glioma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 29278854
2020 miR-185 inhibits prostate cancer angiogenesis induced by the nodal/ALK4 pathway. BMC urology 18 32366240
2018 Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways. Oncogene 18 30061637
2022 Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration. eLife 17 35323108
2019 Bta-miR-24-3p Controls the Myogenic Differentiation and Proliferation of Fetal, Bovine, Skeletal Muscle-Derived Progenitor Cells by Targeting ACVR1B. Animals : an open access journal from MDPI 17 31652908
2019 Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution. American journal of respiratory cell and molecular biology 16 30335480
2022 Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization. The EMBO journal 15 35730718
2019 ALK4-SMAD2/3-SMAD4 signaling mediates the activin A-induced suppression of PTX3 in human granulosa-lutein cells. Molecular and cellular endocrinology 15 31185247
2009 Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor. Journal of peptide science : an official publication of the European Peptide Society 14 19035567
2012 Generation of a conditional mouse model to target Acvr1b disruption in adult tissues. Genesis (New York, N.Y. : 2000) 13 23109354
2022 Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy. Nucleic acid therapeutics 12 36269327
2019 ALK4/5-dependent TGF-β signaling contributes to the crosstalk between neurons and microglia following axonal lesion. Scientific reports 12 31053759
2016 Activin A Stimulates Aromatase via the ALK4-Smad Pathway in Endometriosis. BioMed research international 12 27833918
2015 Conformational features and binding affinities to Cripto, ALK7 and ALK4 of Nodal synthetic fragments. Journal of peptide science : an official publication of the European Peptide Society 12 25588905
2020 CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress. Breast cancer research : BCR 10 33187540
1999 A short loop on the ALK-2 and ALK-4 activin receptors regulates signaling specificity but cannot account for all their effects on early Xenopus development. The Journal of biological chemistry 10 10075688
2022 Activin A promotes human trophoblast invasion by upregulating integrin β3 via ALK4-SMAD4 signaling. Placenta 8 36244196
2020 ALK4-SMAD3/4 mediates the effects of activin A on the upregulation of PAI-1 in human granulosa lutein cells. Molecular and cellular endocrinology 8 31982478
2019 Expression of TGFBR1, TGFBR2, TGFBR3, ACVR1B and ACVR2B is altered in ovaries of cows with cystic ovarian disease. Reproduction in domestic animals = Zuchthygiene 8 30120850
2020 ALK4 coordinates extracellular and intrinsic signals to regulate development of cortical somatostatin interneurons. The Journal of cell biology 6 31676717
2011 Activin A Stimulates Mouse APCs to Express BAFF via ALK4-Smad3 Pathway. Immune network 6 22039367
2023 The effect of ACVR1B/TGFBR1/ACVR1C signaling inhibition on oocyte and granulosa cell development during in vitro growth culture. The Journal of reproduction and development 5 37722883
2022 Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors. The Journal of biological chemistry 5 36403856
2022 Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells. Biomolecules 5 36551177
2005 Developmental analysis of activin-like kinase receptor-4 (ALK4) expression in Xenopus laevis. Developmental dynamics : an official publication of the American Association of Anatomists 5 15614766
2025 Cripto-1 acts as a molecular bridge linking nodal to ALK4 via distinct structural domains. Protein science : a publication of the Protein Society 4 39840816
2024 Acvr1b Loss Increases Formation of Pancreatic Precancerous Lesions From Acinar and Ductal Cells of Origin. Cellular and molecular gastroenterology and hepatology 4 39111635
2021 Activin A and ALK4 Identified as Novel Regulators of Epithelial to Mesenchymal Transition (EMT) in Human Epicardial Cells. Frontiers in cell and developmental biology 4 34977017
2021 Inhibitors of TGFβR1/ALK4/JNK3/Flt1 Kinases in Cynomolgus Macaques Lead to the Rapid Induction of Renal Epithelial Tumors. Toxicological sciences : an official journal of the Society of Toxicology 2 33483736
2021 Activin a inhibits foam cell formation and up-regulates ABCA1 and ABCG1 expression through Alk4-Smad signaling pathway in RAW 264.7 macrophages. Steroids 2 34237315
2021 Implication of rare genetic variants of NODAL and ACVR1B in congenital heart disease patients from Indian population. Experimental cell research 2 34666056
2021 Direct TGF-ß signaling via alk4/5/7 pathway is involved in gut bending in sea urchin embryos. Developmental dynamics : an official publication of the American Association of Anatomists 2 34816532
2025 Activin A-Activated ALK4 Induces Pathogenic Th17-Involved Endothelial-Mesenchymal Transition in Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension. Arthritis & rheumatology (Hoboken, N.J.) 1 40395196
2025 Repair of female reproductive function by GDF-9-overexpressing extracellular vesicles via ACVR1B/SMAD2 regulation in ovarian granulosa. Science advances 1 41370396
2024 Reduced myotube diameter induced by combined inhibition of transforming growth factor-β type I receptors Acvr1b and Tgfbr1 is associated with enhanced β1-syntrophin expression. Journal of cellular physiology 1 39164996
2024 Genetic insights into endurance athlete status: A meta-analysis of ACVR1B, AGT, FTO, IL-6, and NRF2 gene polymorphisms. Journal of biological methods 1 39544188
2023 Abundance of ACVR1B transcript is elevated during septic conditions: Perspectives obtained from a hands-on reductionist investigation. Frontiers in immunology 1 37020544
2022 The activin receptor ligand trap ActRIIB:ALK4-Fc ameliorates cardiomyopathy induced by neuromuscular disease and diabetes. FEBS letters 1 35920165
2022 [Up-regulated expression of miR-576 inhibits ALK4 expression, regulates JAK/STAT signaling pathway and promotes proliferation and migration of prostatic cancer cells]. Zhonghua nan ke xue = National journal of andrology 1 37462480
2020 [Involvement of Notch1 and ALK4/5 Signaling Pathways in Renal Tubular Cell Death: Their Application to Clarification of Cadmium Toxicity]. Nihon eiseigaku zasshi. Japanese journal of hygiene 1 33342936
2025 Activin A exacerbates neonatal necrotizing enterocolitis via ALK4-mediated apoptosis and barrier disruption. International immunopharmacology 0 40494204
2025 Targeting the Alk4 pathway protects against age-related bone loss. bioRxiv : the preprint server for biology 0 41278748
2025 Loss of ALK4 promotes cancer progression through regulating TGF-β receptor N-glycosylation. Nature communications 0 41408046