Affinage

Showing ACVR1B — ALK4 is a alias.

ACVR1B

Activin receptor type-1B · UniProt P36896

Length
505 aa
Mass
56.8 kDa
Annotated
2026-06-09
76 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACVR1B (ALK4) is a type I activin receptor that transduces signals from activins, Nodal, and related TGF-β superfamily ligands by forming heteromeric complexes with type II activin receptors and phosphorylating SMAD2/3 to drive transcriptional responses governing embryonic patterning and tissue homeostasis (PMID:9512518, PMID:9367435, PMID:26305619). Ligand engagement occurs through a defined hydrophobic surface on the ALK4 extracellular domain (Leu40, Ile70, Val73, Leu75, Pro77) that binds activin-A in the presence of a type II receptor (PMID:12665502, PMID:15123686), while Nodal signaling additionally requires the co-receptor Cripto-1, which bridges Nodal (bound to ActRIIB) to ALK4 via its EGF-like and CFC domains to assemble a SMAD2/3-activating ternary complex (PMID:11485994, PMID:11909953, PMID:39840816). Signaling specificity is encoded both in a kinase-subdomain IV–V loop that confers dorsal mesoderm-inducing capacity (PMID:9367435, PMID:10075688) and in selective downstream use of SMAD2 versus SMAD3, with SMAD3-biased output controlling distinct gene programs and, in some contexts, SMAD-independent signaling occurring through ALK4 (PMID:26305619, PMID:20226172). Across tissues, ALK4 sets the balance between proliferation/differentiation and quiescence: it is required for gastrulation and left-right axis determination (PMID:9512518, PMID:15063168), restrains skeletal muscle growth in cooperation with TGFβRI (PMID:35323108), suppresses adipocyte precursor differentiation via CEBPα/PPARγ (PMID:36403856), drives activin A-induced trophoblast invasion through SNAIL/MMP2 and integrin upregulation (PMID:26305619, PMID:33230889, PMID:36244196), and mediates atrial fibrosis (PMID:28639003). In the nucleus accumbens, ALK4 signaling directs SMAD2/SATB1 and SMAD3/PCBP1 partnerships controlling somatostatin interneuron specification and cocaine-induced ΔFosB induction (PMID:31676717, PMID:35730718). ALK4 acts as a tumor suppressor: it is somatically mutated in pancreatic carcinoma (PMID:11248065), and its loss cooperates with Kras to promote pancreatic neoplasia (PMID:39111635) and accelerates breast and pancreatic cancer progression by elevating MGAT5-dependent N-glycosylation that stabilizes surface TGF-β receptors and amplifies canonical TGF-β signaling (PMID:41408046). The small molecule SB-431542 selectively inhibits ALK4/5/7 kinase activity, a tool widely used to dissect this pathway (PMID:12065756).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1997 High

    Established that ALK4 signaling alone can establish threshold mesodermal responses and specify dorsal/anterior fates, distinguishing it from ventralizing ALK2 signaling.

    Evidence Constitutively active receptor mRNA injection and gene expression analysis in Xenopus animal caps

    PMID:9367435

    Open questions at the time
    • Identity of endogenous ligands driving dorsal induction in vivo not resolved
    • Downstream transcriptional mechanism not defined
  2. 1998 High

    Demonstrated genetically that ALK4 forms complexes with type II activin receptors and is required for gastrulation and primitive streak formation, anchoring its developmental role.

    Evidence Gene targeting/knockout and chimera analysis in mice

    PMID:9512518

    Open questions at the time
    • Does not distinguish which ligand(s) act through ALK4 at gastrulation
    • Molecular basis of streak requirement not addressed
  3. 1999 Medium

    Mapped signaling specificity to a seven-residue kinase subdomain IV–V loop, showing receptor specificity is encoded intracellularly rather than solely by ligand binding.

    Evidence Chimeric receptor construction and Xenopus animal cap assay

    PMID:10075688

    Open questions at the time
    • Structural basis of how the loop dictates SMAD/effector selection unknown
    • Single lab, single study
  4. 2000 High

    Defined a disease-relevant dominant-negative mechanism whereby truncated ALK4 isoforms in pituitary tumors sequester type II receptors and block antiproliferative activin signaling.

    Evidence Reciprocal Co-IP, reporter and proliferation assays in transfected cells

    PMID:11117535

    Open questions at the time
    • In vivo contribution of truncated isoforms to tumorigenesis not tested
    • Generality across tumor types unknown
  5. 2001 High

    Showed ALK4 mediates Nodal signaling only with the co-receptor Cripto, and is the obligate type I receptor for a broad set of mesoderm-inducing ligands, defining its ligand range.

    Evidence Receptor reconstitution, Co-IP, and dominant-negative epistasis in Xenopus; somatic mutation sequencing in pancreatic cancer

    PMID:11248065 PMID:11485994

    Open questions at the time
    • Stoichiometry of the Nodal–Cripto–ALK4 complex not resolved at this stage
    • Functional consequence of pancreatic somatic mutations on receptor activity not directly tested
  6. 2002 High

    Established Cripto-1 as a direct ALK4-binding co-receptor that gates Nodal-dependent SMAD2 phosphorylation, while Cripto's MAPK/AKT activation is ALK4-independent.

    Evidence Phage display, Co-IP, FACS, and reporter assays in mammalian epithelial cells

    PMID:11909953

    Open questions at the time
    • Domain-level interface not yet defined
    • Quantitative affinity not measured
  7. 2002 High

    Provided a selective pharmacological tool by showing SB-431542 inhibits ALK4/5/7 but not other ALKs or MAPK pathways, enabling specific dissection of SMAD2/3 signaling.

    Evidence In vitro kinase assays and cell-based signaling readouts

    PMID:12065756

    Open questions at the time
    • Cannot distinguish ALK4 from ALK5/ALK7 within the pathway
    • No structural basis for selectivity provided
  8. 2003 High

    Defined the activin-A binding surface on ALK4 at the residue level and confirmed binding requires the type II receptor, linking structure to ligand engagement.

    Evidence Site-directed mutagenesis, dominant-negative assays, and 125I-activin-A crosslinking

    PMID:12649175 PMID:12665502

    Open questions at the time
    • No co-crystal structure of the ternary ligand–receptor complex
    • Whether the same surface engages other ligands not tested
  9. 2004 High

    Confirmed ALK4 as the type I receptor selectively engaged by activin-A and myostatin (but not TGF-β) and demonstrated ligand-specific use of ALK4 in left-right axis determination.

    Evidence Activin-A mutant crosslinking and antagonism assays; Co-IP and dominant-negative/morpholino epistasis in Xenopus

    PMID:15063168 PMID:15123686

    Open questions at the time
    • Mechanism that channels Vg1 but not Xnr1/derriere to ALK4 unknown
    • Type II receptor partner specificity not dissected
  10. 2009 Medium

    Characterized the Cripto CFC–ALK4 interface structurally, identifying the micromolar binding mode and key exposed residues.

    Evidence Synthetic CFC domain, NMR, SPR binding, and molecular docking

    PMID:19035567

    Open questions at the time
    • No cellular mutagenesis validation of docking-predicted contacts
    • Affinity is low/micromolar, physiological relevance of isolated domain unclear
  11. 2010 Medium

    Demonstrated a tissue-homeostatic role: keratinocyte ALK4 is required for hair follicle cycling and restrains epidermal proliferation.

    Evidence Keratinocyte-specific conditional knockout with histology

    PMID:21191412

    Open questions at the time
    • Ligand and SMAD effector driving the phenotype not identified
    • Molecular target genes not defined
  12. 2015 High

    Resolved a complete signaling-to-phenotype axis for trophoblast invasion, with ALK4–SMAD2/3–SMAD4 upregulating SNAIL and then MMP2.

    Evidence siRNA knockdown of multiple pathway components, expression analysis, and Matrigel invasion assays

    PMID:26305619

    Open questions at the time
    • In vivo relevance to placentation not tested
    • Direct SMAD binding to SNAIL promoter not shown here
  13. 2017 Medium

    Established ALK4 as a driver of pathological fibrosis, with ALK4-deficient mice protected from atrial fibrosis and arrhythmia.

    Evidence ALK4 haplodeficiency mouse model with electrophysiology and histology

    PMID:28639003

    Open questions at the time
    • Cell-autonomous versus paracrine contribution not fully separated
    • Downstream profibrotic transcriptional targets not defined
  14. 2016 Medium

    Revealed dual, context-dependent ALK4 roles in muscle, where knockdown enhances myoblast differentiation in vitro yet promotes atrophy in vivo.

    Evidence Antisense oligonucleotide knockdown with in vitro/in vivo functional readouts and RNAseq in mdx mice

    PMID:27733450

    Open questions at the time
    • Reconciliation of opposing in vitro/in vivo effects mechanistically unresolved
    • Contribution of redundant type I receptors not addressed
  15. 2020 Medium

    Defined neuronal ALK4 mechanisms in the nucleus accumbens, showing SMAD2-driven SATB1 nuclear repositioning controls somatostatin interneuron specification.

    Evidence Conditional knockout, Co-IP, nuclear fractionation, and immunostaining

    PMID:31676717

    Open questions at the time
    • Upstream ligand in MSNs not defined
    • Direct SMAD2–SATB1 binding interface not mapped
  16. 2020 Medium

    Demonstrated SMAD2/3 effector specificity and SMAD-independent ALK4 output, with distinct SMAD2-, SMAD3-, and SMAD-independent programs across cell types.

    Evidence siRNA knockdown, ChIP, nuclear fractionation, and functional assays in trophoblast, neuroblastoma, granulosa, and renal cells

    PMID:20226172 PMID:30804470 PMID:31185247 PMID:33230889

    Open questions at the time
    • Molecular basis selecting SMAD2 vs SMAD3 vs SMAD-independent output unknown
    • Many contexts rely on a single lab
  17. 2022 High

    Established ALK4 as a redundant brake on skeletal muscle growth: combined Tgfbr1/Acvr1b deletion triggers hypertrophy via Akt/p70S6K and reduced E3 ligases, while single deletion does not.

    Evidence Muscle-specific double conditional knockout with phospho-Western, histology, and injury models

    PMID:35323108

    Open questions at the time
    • Ligand redundancy upstream not fully resolved
    • Whether SMAD or non-SMAD signaling enforces the brake not separated
  18. 2022 High

    Expanded ALK4's homeostatic roles to adipose hyperplasia, with ALK4 suppressing precursor differentiation through CEBPα/PPARγ, and consolidated cocaine-related ΔFosB induction via SMAD3–PCBP1.

    Evidence Conditional knockout with rescue (CEBPα knockdown); conditional KO, Co-IP, RIP, and behavioral sensitization

    PMID:35730718 PMID:36403856

    Open questions at the time
    • Ligand driving adipose precursor ALK4 signaling not identified
    • How D1 signaling converges on ALK4/SMAD3 mechanistically incomplete
  19. 2024 Medium

    Established ALK4 as a Kras-cooperating pancreatic tumor suppressor whose loss promotes precancerous lesions from acinar and ductal cells, accelerated by pancreatitis.

    Evidence Cell-type-specific conditional knockouts with MRI and histopathology

    PMID:39111635

    Open questions at the time
    • Molecular tumor-suppressive mechanism not defined in this study
    • Progression to invasive carcinoma not quantified
  20. 2025 Medium

    Provided a molecular mechanism for ALK4 tumor suppression: ALK4 loss raises MGAT5-dependent N-glycosylation and galectin-3-mediated stabilization of surface TGF-β receptors, amplifying canonical TGF-β signaling and progression.

    Evidence In vitro KO/knockdown, in vivo cancer models, glycosylation analysis, and MGAT5/galectin-3 rescue experiments

    PMID:41408046

    Open questions at the time
    • How ALK4 controls MGAT5 expression not mechanistically resolved
    • Single lab
  21. 2025 Medium

    Refined the Nodal signaling architecture, showing Cripto-1 bridges Nodal–ActRIIB to ALK4 via distinct EGF-like and CFC domains, contrasting with canonical ligand-bridging.

    Evidence AlphaFold3 modeling, SPR, domain-specific antibodies, and SMAD2/3 assays in NTERA-2 cells

    PMID:39840816

    Open questions at the time
    • No mutagenesis validation of modeled interfaces
    • No experimental structure of the ternary complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what determines ALK4's choice among SMAD2, SMAD3, and SMAD-independent outputs across tissues, and how upstream ligand and type II receptor combinations select these programs.
  • No unifying structural/biochemical model of effector selection
  • Tissue-specific ligand inputs largely inferred rather than mapped
  • Cause-effect link between glycosylation control and SMAD output not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
ACVR2BPCBP1SATB1SMAD2SMAD3SMAD4TDGF1TGFBR1
Complex memberships
ALK4–type II activin receptor (ActRII/IIB) heteromeric receptor complexNodal–Cripto-1–ALK4–ActRIIB ternary signaling complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 ActRIB (ACVR1B) forms heteromeric complexes with type II activin receptors to mediate activin signaling; genetic knockout in mice shows it is required for egg cylinder organization and gastrulation, with chimera analysis demonstrating a role in primitive streak formation but not mesoderm differentiation per se. Gene targeting/knockout, chimera analysis Genes & development High 9512518
1997 Constitutively active ALK4 (ALK-4*) induces dose-dependent mesoderm including dorsal/anterior cell types (goosecoid, Xbra) and endoderm in Xenopus animal caps, whereas ALK-2* induces only ventral mesoderm; threshold responses to activin can be established by ALK4 signaling alone, and ventralizing ALK-2* signals antagonize ALK-4* dorsal signals. Constitutively active receptor mRNA injection, Xenopus animal cap assay, gene expression analysis Development (Cambridge, England) High 9367435
1999 The loop between kinase subdomains IV and V of ALK4 (seven amino acids) mediates its strong dorsal gene-inducing signaling specificity; transferring this loop from ALK4* to ALK2* confers dorsal gene induction on ALK2*, identifying this loop as a key determinant of ALK4 signaling specificity. Chimeric receptor construction, mRNA injection, Xenopus animal cap assay The Journal of biological chemistry Medium 10075688
2000 Truncated ALK4 isoforms (Alk4-2, 4-3, 4-4) found in human pituitary tumors act as dominant-negative receptors: they co-immunoprecipitate with type II activin receptors but are not phosphorylated, blocking wild-type activin signaling and the antiproliferative effects of activin. Coimmunoprecipitation, reporter assays, stable transfection, cell proliferation assay Molecular endocrinology (Baltimore, Md.) High 11117535
2001 ALK4 mediates Nodal signaling (Xnr1, mouse Nodal) only in the presence of the co-receptor Cripto; ALK4 can directly interact with Cripto. A dominant-negative ALK4 blocks all mesoderm-inducing ligands (Nodal, Xnr1, Xnr2, Xnr4, Activin), while dominant-negative ALK7 specifically blocks Nodal/Xnr1. Receptor reconstitution, Co-IP, dominant-negative receptor injection in Xenopus embryos Genes & development High 11485994
2001 ACVR1B harbors somatic mutations in pancreatic carcinoma, establishing it as a mutated tumor-suppressor gene in sporadic pancreatic cancer. Direct sequencing of pancreatic cancer samples 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 cells (identified by phage display and confirmed by co-immunoprecipitation and FACS); Cripto-1 phosphorylates Smad2 only in the presence of both Nodal and ALK4, while Cripto-1-stimulated MAPK and AKT activation is independent of Nodal and ALK4. Phage display library screening, coimmunoprecipitation, FACS, reporter assays Molecular and cellular biology High 11909953
2002 SB-431542 inhibits ALK4, ALK5, and ALK7 kinase activity but has no effect on other ALK family members (ALK1, 2, 3, 6) or on ERK, JNK, or p38 MAP kinase pathways, making it a selective inhibitor of activin/TGF-β/Nodal type I receptor signaling via SMAD2/3. Biochemical kinase inhibition assay, reporter assays, cell signaling analysis Molecular pharmacology High 12065756
2003 Five hydrophobic residues on the ALK4 extracellular domain (Leu40, Ile70, Val73, Leu75, Pro77) constitute a functional binding surface for activin-A; mutation of these residues to alanine substantially disrupts dominant-negative ALK4 activity and reduces 125I-activin-A crosslinking to ALK4 in the presence of ActRII. Site-directed mutagenesis, dominant-negative inhibition assay, 125I-activin crosslinking The Journal of biological chemistry High 12665502
2003 Cripto-1 activates MAPK and AKT pathways independently of Nodal and ALK4 by binding to Glypican-1 and activating c-Src; this ALK4-independent pathway is required for CR-1-induced in vitro transformation and migration. Co-immunoprecipitation, kinase assays, migration/transformation assays Cancer research Medium 12649175
2004 An activin-A M108A mutant retains wild-type affinity for ActRII but cannot form a crosslinked complex with ALK4 in the presence of ActRII, indicating disrupted ALK4 binding; this mutant antagonizes activin-A and myostatin but not TGF-β signaling, confirming it as a type II receptor antagonist that blocks ALK4-dependent ligands. In vitro crosslinking, receptor-binding assay, cell-based signaling assay, mutagenesis The Journal of biological chemistry High 15123686
2004 ALK4 co-immunoprecipitates with multiple TGF-β ligands (Activin-Vg1 chimera, Xnr1, derriere, endogenous Vg1); functionally, ALK4 signaling is required for Vg1-mediated LR axis determination but not for Xnr1- or derriere-mediated LR effects, demonstrating ligand-specific utilization of the ALK4 pathway. Co-immunoprecipitation, dominant-negative receptor injection in Xenopus embryos, morpholino knockdown Developmental biology Medium 15063168
2006 Activin B can signal through ALK7 (in addition to ALK4) in immortalized gonadotrope (LβT2) cells to stimulate Fshb transcription; both ALK4(TD) and ALK7(TD) phosphorylate Smad2/3, and the effects of both receptors on Fshb promoter activity require Smad3. RT-PCR, transfection of constitutively active and kinase-dead receptors, reporter assay, siRNA knockdown, Western blot Reproductive biology and endocrinology : RB&E Medium 17040568
2009 The Cripto CFC domain interacts with the extracellular domain of ALK4 with a KD in the micromolar range; NMR structural characterization identifies H120 and W124 as externally exposed residues, and molecular docking indicates these and prior mutagenesis-identified residues contribute to the CFC-ALK4 protein-protein interface. Chemical synthesis of CFC domain, NMR spectroscopy, SPR binding assay, molecular docking Journal of peptide science Medium 19035567
2010 Conditional keratinocyte-specific knockout of Acvr1b (K14-Cre) causes hair follicle cycling defects and progressive hair loss, as well as persistent epidermal cell proliferation, demonstrating that Acvr1b signaling is required for hair follicle cycling and skin epithelial homeostasis. Conditional knockout (Cre-lox), histological analysis The Journal of investigative dermatology Medium 21191412
2013 Inhibition of ALK4/ALK7 signaling (but not ALK5 alone) in developing mouse testis impairs male germ cell differentiation and mitotic arrest entry, while ALK4/5/7 inhibition blocks testis cord formation during the sex-determining period; Nodal is specifically expressed in male germ cells and Nanog expression is reduced when ALK4/5/7 signaling is blocked. Pharmacological inhibition (SB431542), FACS-purified gonadal cell gene expression analysis PloS one Medium 23342175
2015 Activin A induces human trophoblast invasion by activating ALK4–SMAD2/3–SMAD4 signaling to upregulate SNAIL, which then transcriptionally induces MMP2; siRNA knockdown of ALK4, SMAD2/3, or SMAD4 abolishes activin A-induced SNAIL and MMP2 production and trophoblast invasion. siRNA knockdown, Western blot, RT-qPCR, Matrigel invasion assay The Journal of clinical endocrinology and metabolism High 26305619
2016 ALK4 knockdown via antisense oligonucleotides in mdx mice reduces Alk4 expression, inhibits myostatin activity, and increases myoblast differentiation in vitro; paradoxically, in vivo Alk4 inhibition reduces muscle mass (~10%) and increases signs of muscle atrophy, demonstrating ALK4 plays dual roles in muscle atrophy and regeneration. Antisense oligonucleotide exon skipping, in vitro differentiation assay, in vivo muscle mass measurement, RNAseq FASEB journal Medium 27733450
2017 ALK4 mediates activin A/ALK4/Smad2/3 signaling in atrial fibroblasts; ALK4-deficient mice subjected to angiotensin-II show reduced atrial fibroblast activation, blunted atrial enlargement and fibrosis, and reduced atrial fibrillation vulnerability compared to wild-type littermates. ALK4 haplodeficiency mouse model, electrophysiological studies, histology, immunostaining Basic research in cardiology Medium 28639003
2019 ALK4-mediated Smad3 (but not Smad2) phosphorylation promotes cadmium-induced cell death in renal proximal tubular HK-2 cells via Akt signaling; siRNA knockdown of ALK4 or Smad3, or treatment with SIS3 (Smad3 inhibitor), suppresses cadmium-induced cell death. Separately, ALK4/5 blockade protects against erastin-induced ferroptosis by hyperactivating Nrf2 signaling. siRNA knockdown, pharmacological inhibition, Western blot, cell viability assay Cell death and differentiation Medium 30804470
2019 ALK4-SMAD2/3-SMAD4 signaling mediates activin A-induced suppression of PTX3 expression in human granulosa-lutein cells; phosphorylated SMADs bind directly to the PTX3 promoter as demonstrated by ChIP analysis. siRNA knockdown, Western blot, RT-qPCR, ChIP assay Molecular and cellular endocrinology Medium 31185247
2020 ALK4 signaling in medium spiny neurons (MSNs) of the nucleus accumbens induces SMAD2 interaction with SATB1, promoting SATB1 nuclear translocation and repositioning within the somatostatin gene promoter; ALK4 loss-of-function in MGE GABAergic neurons reduces specific somatostatin interneuron subpopulations in the cortex. Conditional knockout, co-immunoprecipitation, nuclear fractionation, immunostaining The Journal of cell biology Medium 31676717
2020 Activin A increases trophoblast invasion by upregulating integrin β1 expression through ALK4-activated SMAD2/3-SMAD4 pathway; siRNA knockdown of ALK4 or SMAD4 abolishes activin A-induced integrin β1 upregulation and the increase in cell invasion. siRNA knockdown, Western blot, RT-qPCR, Matrigel invasion assay FASEB journal Medium 33230889
2020 Activin A induces neuronal differentiation and survival in SK-N-SH neuroblastoma cells via ALK4, but in a SMAD-independent manner: activin A does not induce SMAD2/3 phosphorylation, SMAD2/3-SMAD4 interaction, nuclear SMAD accumulation, or SMAD DNA binding in this context, yet still transactivates TGF-β target genes through ALK4. Western blot, co-immunoprecipitation, nuclear fractionation, ChIP, siRNA knockdown, neurite outgrowth assay Biochemical and biophysical research communications Medium 20226172
2020 Activin A promotes remyelination after ischemic stroke through oligodendroglial ACVR1B; AAV-based ACVR1B shRNA with Olig2 promoter reverses activin A-induced increases in oligodendrocyte number, LFB staining intensity, myelin proteins (MAG, MOG, MBP), and neurological function recovery. AAV-shRNA knockdown, immunostaining, Western blot, behavioral assays in MCAO/R mouse model Experimental neurology Medium 33345977
2021 ActRIIB:ALK4-Fc, a heterodimeric fusion protein combining extracellular domains of ALK4 and ActRIIB, has a distinct ligand-binding profile from homodimeric ActRIIB-Fc (by SPR): it sequesters ActRIIB ligands that inhibit muscle growth but does not trap BMP9; it improves muscle mass, function, and NMJ abnormalities in murine DMD, ALS, and disuse atrophy models. Surface plasmon resonance, in vivo mouse models (DMD, ALS, disuse atrophy), muscle function assays, histology The Journal of clinical investigation High 33586684
2022 Dopamine D1 receptor signaling synergizes with activin/ALK4/Smad3 signaling to potentiate ΔFosB mRNA generation in nucleus accumbens MSNs via activation of RNA-binding protein PCBP1; concurrent D1 and ALK4 activation induces PCBP1-Smad3 interaction, nuclear translocation, and binding to FosB exon-4/intron-4. ALK4 ablation in MSNs impairs ΔFosB induction and behavioral sensitization to cocaine. Conditional knockout, co-immunoprecipitation, nuclear fractionation, RIP (RNA immunoprecipitation), behavioral sensitization assay The EMBO journal High 35730718
2022 Simultaneous muscle-specific double knockout of Tgfbr1 and Acvr1b in mice induces substantial skeletal muscle hypertrophy (single knockouts do not), mediated by increased Akt/p70S6K phosphorylation and reduced E3 ligase expression; double KO also increases satellite cell and macrophage numbers and improves post-injury regeneration. Double conditional knockout, phospho-Western blot, histology, cardiotoxin injury model eLife High 35323108
2022 ALK4 is preferentially expressed in adipocyte precursors where it suppresses differentiation by inhibiting CEBPα and PPARγ expression; ALK4 deletion induces premature adipocyte differentiation rescued by CEBPα knockdown, establishing that ALK4 promotes adipose tissue hyperplasia by restraining precursor differentiation. Conditional knockout, siRNA knockdown, gene expression analysis, adipocyte differentiation assay The Journal of biological chemistry Medium 36403856
2022 Activin A modulates betaglycan shedding via the ALK4-SMAD3 (but not SMAD2)-dependent pathway in endometriotic cells; activin A stimulation reduces soluble betaglycan release in an ALK4/SMAD3-dependent manner confirmed by siRNA knockdown and specific inhibitors. siRNA knockdown, pharmacological inhibition (LY364947/SIS3), ELISA, Western blot Biomolecules Medium 36551177
2022 Activin A promotes trophoblast invasion by upregulating integrin β3 via ALK4-SMAD4 signaling; siRNA knockdown of ALK4 or SMAD4 abolishes activin A-upregulated integrin β3 expression in both immortalized and primary EVT cells. siRNA knockdown, Western blot, RT-qPCR, invasion assay Placenta Medium 36244196
2024 Loss of Acvr1b (in the presence of Kras oncogene) promotes development of pancreatic intraepithelial neoplasia and IPMN-like precancerous lesions from both acinar and ductal cells, and acute pancreatitis accelerates precancerous lesion development specifically when acinar cells carry both mutations. Conditional knockout (Ptf1aCreER and Sox9CreER), MRI, histopathology, immunohistochemistry Cellular and molecular gastroenterology and hepatology Medium 39111635
2025 Cripto-1 acts as a molecular bridge linking Nodal to ALK4: Nodal, bound to type II receptor ActRIIB, uses Cripto-1 (via its EGF-like domain for Nodal binding and CFC domain for ALK4 binding) to recruit ALK4 and form a ternary complex for SMAD2/3 activation; this contrasts with canonical TGF-β ligand-bridging of type I and II receptors. AlphaFold3 modeling, surface plasmon resonance, domain-specific antibodies, functional SMAD2/3 signaling assay in NTERA-2 cells Protein science : a publication of the Protein Society Medium 39840816
2025 ALK4 loss promotes cancer progression (enhanced anchorage-independent growth, migration, invasion, EMT) in breast and pancreatic cancer models by increasing N-linked glycosylation of TGF-β receptors via MGAT5 upregulation; galectin-3 binds MGAT5-modified glycoproteins to stabilize surface TGF-β receptors, enhancing canonical TGF-β signaling. Depleting MGAT5 or inhibiting N-glycosylation suppresses ALK4-loss-induced TGF-β signaling. In vitro KO/knockdown, in vivo cancer models, glycosylation analysis, MGAT5/galectin-3 siRNA knockdown, N-glycosylation inhibition Nature communications Medium 41408046
2025 ALK4 deletion in osteoblast progenitors (Alk4 cKO mice) increases trabecular bone acquisition, osteoblast number, and bone formation rate; mice are protected against early age-related trabecular bone loss, and an Alk4-Fc ligand trap prevents bone loss in aged mice, indicating Activin/ALK4 signaling suppresses osteoblast activity. Conditional knockout, bone histomorphometry, ligand trap injection in aged mice, micro-CT bioRxivpreprint Medium 41278748
2025 Activin A activates ALK4 in Th17 cells and pulmonary microvascular endothelial cells (PMECs); ALK4 overexpression in Th17 cells increases IL-6 and CTGF in co-cultured PMECs and induces EndoMT; ALK4 activates pSmad2 and pSTAT3 to drive CTGF transcription, and ALK4 inhibitor vactosertib (TEW-7197) suppresses this pathway. ALK4 overexpression, co-culture, mouse model, ALK4 inhibitor, Western blot, ELISA Arthritis & rheumatology (Hoboken, N.J.) Low 40395196
2016 Activin A stimulates aromatase (P450arom) expression and estradiol secretion in endometrial stromal cells from endometriosis patients via the ALK4-Smad pathway; effects are partially abrogated by an ALK4 inhibitor and Smad4-siRNA knockdown. Pharmacological inhibition (ALK4 inhibitor), siRNA knockdown, RT-qPCR, Western blot BioMed research international Low 27833918
2011 Activin A enhances BAFF expression in mouse macrophages and dendritic cells via ALK4-Smad3 pathway; ALK4 kinase inhibitor SB431542 and dominant-negative Smad3 both abolish activin A-induced BAFF transcription. RT-PCR, ELISA, pharmacological inhibition (SB431542), dominant-negative Smad3 transfection Immune network Low 22039367
2020 ALK4-SMAD3-SMAD4 (but not SMAD2 alone for all effects) mediates activin A-induced upregulation of PAI-1 in human granulosa-lutein cells, as demonstrated by siRNA knockdown of ALK4, SMAD3, and SMAD4 each individually abolishing the effect. siRNA knockdown, Western blot, RT-qPCR, ELISA Molecular and cellular endocrinology Low 31982478
2021 Activin A inhibits ox-LDL-induced foam cell formation and upregulates ABCA1/ABCG1 in RAW 264.7 macrophages via Alk4-Smad2 signaling; SB-431542 abolishes these effects and Smad2 knockdown reverses inhibition of ox-LDL uptake, while Smad3 or Smad4 knockdown does not affect uptake but does reverse ABCA1/ABCG1 upregulation. SB-431542 pharmacological inhibition, siRNA knockdown, Western blot, RT-qPCR, confocal microscopy Steroids Low 34237315
2025 GDF-9-overexpressing extracellular vesicles activate ACVR1B, which induces SMAD2 phosphorylation and nuclear translocation in granulosa cells to rescue ovarian function in aging mice. siRNA/genetic modification of EVs, Western blot for SMAD2 phosphorylation and nuclear fractionation, in vivo ovarian function assays Science advances Low 41370396

Source papers

Stage 0 corpus · 76 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 1444 12065756
2004 SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Molecular pharmacology 352 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 190 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 174 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
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 72 28639003
2013 Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PloS one 71 23342175
2015 Activin A Increases Human Trophoblast Invasion by Inducing SNAIL-Mediated MMP2 Up-Regulation Through ALK4. The Journal of clinical endocrinology and metabolism 66 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 60 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 37 21063444
2020 Activin A improves the neurological outcome after ischemic stroke in mice by promoting oligodendroglial ACVR1B-mediated white matter remyelination. Experimental neurology 33 33345977
2015 Late Alk4/5/7 signaling is required for anterior skeletal patterning in sea urchin embryos. Development (Cambridge, England) 30 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
2021 ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders. The Journal of clinical investigation 27 33586684
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
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
2020 miR-185 inhibits prostate cancer angiogenesis induced by the nodal/ALK4 pathway. BMC urology 19 32366240
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
2022 Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration. eLife 18 35323108
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
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
2022 Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization. The EMBO journal 16 35730718
2019 Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution. American journal of respiratory cell and molecular biology 16 30335480
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
2019 ALK4/5-dependent TGF-β signaling contributes to the crosstalk between neurons and microglia following axonal lesion. Scientific reports 13 31053759
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
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 11 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
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 6 37722883
2022 Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells. Biomolecules 6 36551177
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
2022 Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors. The Journal of biological chemistry 5 36403856
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
2026 RUNX1-mediated repression of miR-24 promotes hepatic stellate cell activation and liver fibrosis by targeting the ALK4/Smad3 signaling pathway. Frontiers in genetics 0 42137245
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

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