Affinage

ACVR1C

Activin receptor type-1C · UniProt Q8NER5

Length
493 aa
Mass
54.9 kDa
Annotated
2026-04-28
54 papers in source corpus 31 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that transduces signals from multiple ligands—Nodal, activin B, activin AB, GDF3, and activin E (INHBE)—through phosphorylation of Smad2/3 to regulate diverse processes including adipose metabolism, pancreatic β-cell function, neuronal differentiation, cardiac homeostasis, reproductive neuroendocrine circuits, and tumor suppression. In adipose tissue, ALK7 suppresses β-adrenergic receptor expression and lipolysis, and its genetic ablation confers resistance to diet-induced obesity and enhances energy expenditure by upregulating β3-AR/C/EBPα and mitochondrial biogenesis (PMID:25161195, PMID:37523551, PMID:38307384). In pancreatic β-cells, activin B–ALK7 signaling negatively regulates glucose-stimulated insulin secretion through modulation of Ca²⁺ influx, while Nodal–ALK7 signaling induces apoptosis via Smad2/3-dependent caspase-3 activation and Akt/XIAP suppression (PMID:18480258, PMID:22550067). ALK7 also functions as a tumor suppressor barrier—activin B–ALK7 induces apoptosis in neoplastic cells, and cancer cells evade this by downregulating ALK7 or its ligands—though in pancreatic ductal adenocarcinoma ALK7 can paradoxically promote metastasis through non-canonical β-catenin–MMP pathways (PMID:31063757, PMID:40616087).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    The first mechanistic evidence that ALK7 signals through the Smad pathway was established when constitutively active ALK7 was shown to activate Smad2 and Smad3 (but not Smad1) and drive their nuclear translocation, defining ALK7 as an activin/TGF-β-branch type I receptor.

    Evidence Constitutively active ALK7 transfection with chimeric Smad constructs, nuclear translocation assays, and PAI-1 promoter-reporter in cell lines

    PMID:9920806

    Open questions at the time
    • Single study without identification of the endogenous ligand
    • Domain requirements for Smad2 vs Smad3 activation not independently validated
  2. 2000 High

    ALK7 was shown to have pleiotropic cellular effects beyond Smad activation—inducing growth arrest (via p15INK4B/p21), ERK/JNK activation, and neuronal differentiation—establishing it as a multifunctional signaling receptor.

    Evidence Tetracycline-inducible constitutively active ALK7 in PC12 cells with proliferation, reporter, and morphological assays

    PMID:11084022

    Open questions at the time
    • Endogenous ligand for ALK7 in neuronal cells not identified
    • ERK/JNK activation mechanism (direct vs indirect) unresolved
  3. 2001 High

    The identity of ALK7's physiological ligand was resolved when Nodal was shown to signal through an ALK7/ActRIIB complex, with the co-receptor Cripto greatly enhancing responsiveness, explaining how Nodal achieves cell-type-specific signaling.

    Evidence Receptor reconstitution, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays

    PMID:11485994

    Open questions at the time
    • Whether ALK7 has Nodal-independent ligands was unknown
    • Structural basis of Cripto-ALK7 interaction unresolved
  4. 2002 High

    Development of selective small-molecule inhibitors (SB-431542) that block ALK4/5/7 kinase activity provided pharmacological tools confirming ALK7's kinase-dependent signaling mechanism and enabling pathway dissection.

    Evidence In vitro kinase assay and cell-based signaling assays with extensive selectivity profiling

    PMID:12065756

    Open questions at the time
    • SB-431542 cannot distinguish ALK7 from ALK4/ALK5 effects
    • No ALK7-selective inhibitor developed
  5. 2004 High

    The ligand repertoire of ALK7 was expanded beyond Nodal when activin B and activin AB were identified as ALK7 ligands that preferentially pair with ActRIIA (not ActRIIB), and this combination was shown to regulate insulin secretion in β-cells—establishing ALK7's metabolic role.

    Evidence Receptor reconstitution in cell lines with insulin secretion functional readout; parallel Nodal-ALK7 apoptosis studies in trophoblast

    PMID:15150278 PMID:15196700

    Open questions at the time
    • In vivo validation of activin B–ALK7 axis in β-cells pending
    • Downstream mechanism linking ALK7 to insulin exocytosis machinery unknown
  6. 2004 High

    ALK7 knockout mice developed normally without left-right patterning defects, demonstrating that ALK7 is dispensable for canonical Nodal functions in embryogenesis and redirecting the field toward tissue-specific metabolic and neurological roles.

    Evidence Global ALK7 knockout mouse generation with comprehensive histological and compound mutant analysis

    PMID:15485907

    Open questions at the time
    • Metabolic phenotypes of knockout not yet characterized
    • Compensatory mechanisms by ALK4 not excluded
  7. 2008 High

    Genetic epistasis with activin B and ALK7 double knockouts proved they function in a common pathway to negatively regulate glucose-stimulated insulin secretion through Ca²⁺ signaling, while parallel studies showed GDF3 signals through ALK7/Cripto to regulate adipose accumulation.

    Evidence Single and double knockout mice with calcium imaging, insulin secretion, and high-fat diet metabolic phenotyping

    PMID:18480258 PMID:18480259

    Open questions at the time
    • Molecular link between ALK7-Smad and Ca²⁺ channel regulation not identified
    • Relative contributions of activin B vs GDF3 in adipose tissue unclear
  8. 2014 High

    The central adipose mechanism was established: ALK7 mediates diet-induced catecholamine resistance by suppressing β-adrenergic receptor expression and lipolysis cell-autonomously, and acute chemical-genetic inhibition recapitulated genetic ablation effects, validating ALK7 as a druggable anti-obesity target.

    Evidence Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, β-AR signaling and lipolysis assays in mouse and human adipocytes

    PMID:25161195

    Open questions at the time
    • Mechanism by which Smad2/3 suppresses β-AR transcription not defined
    • Human genetic validation lacking
  9. 2015 Medium

    ALK7 was shown to protect against pathological cardiac hypertrophy through MEK-ERK1/2 inhibition, and separately to regulate brown adipocyte differentiation via Smad3-PPARγ signaling, revealing tissue-specific non-canonical pathway usage.

    Evidence Cardiac-specific transgenic and knockout mice with aortic banding; brown adipocyte differentiation assays with pharmacological/genetic tools

    PMID:26249805 PMID:26266090

    Open questions at the time
    • Single-lab cardiac studies await independent replication
    • Whether ALK7 directly inhibits MEK-ERK or acts through an intermediate not resolved
    • Brown adipocyte findings not confirmed in vivo
  10. 2019 High

    ALK7 was established as a tumor suppressor: activin B–ALK7 induces apoptosis as a barrier to metastatic seeding, and cancer cells evade this by downregulating ALK7 or activin B—while paradoxically, in PDAC, ALK7 signaling destroys endothelial cells contributing to tumor hypovascularity.

    Evidence In vivo mouse models of pancreatic neuroendocrine cancer, luminal breast cancer, and PDAC with genetic ALK7 modulation and organotypic tumor-on-a-chip

    PMID:31063757 PMID:31489365

    Open questions at the time
    • Context-dependent switch from tumor suppressor to pro-metastatic signaling unexplained mechanistically
    • Patient-derived tumor ALK7 expression patterns not systematically characterized
  11. 2021 High

    Activin E (INHBE) was identified as a new ALK7 ligand that suppresses lipolysis via Smad2/3 and PPARγ target gene repression, while separately ALK7 was shown to regulate Mkrn3 expression through Smad2/3-KAP1 epigenetic repression, expanding ALK7's roles to include pubertal timing and epigenetic regulation.

    Evidence Parallel activin E and ACVR1C knockout mice with RNA-seq and lipolysis assays; ChIP for KAP1 and histone marks at Mkrn3 locus

    PMID:34245608 PMID:37523551

    Open questions at the time
    • Whether INHBE is the primary ALK7 ligand in human adipose unknown
    • Mkrn3 regulation validated only in mouse hippocampus, relevance to human puberty not tested
  12. 2024 High

    Human genetic variants in ACVR1C were functionally validated through knock-in mice, showing graded allelic effects on ALK7 signaling and metabolic phenotype—I195T phenocopies null (obesity resistance), I482V is partial, N150H is near-normal—directly connecting human sequence variation to receptor function.

    Evidence Three independent knock-in mouse models with high-fat diet challenge, ALK7 signaling quantification, and lipolysis assays

    PMID:38307384

    Open questions at the time
    • Human population-level metabolic phenotyping of carriers not completed
    • Structural basis for graded signaling defects not resolved
  13. 2024 Medium

    ALK7 was linked to synaptic plasticity and memory: hippocampal Acvr1c overexpression rescued learning deficits in aged and 5xFAD Alzheimer's model mice, with exercise alleviating epigenetic repression at the Acvr1c promoter.

    Evidence RNA-seq of dorsal hippocampus, epigenetic analysis, Acvr1c overexpression, electrophysiology, and behavioral memory tests in mice

    PMID:38714691

    Open questions at the time
    • Single-lab finding in novel context requires independent replication
    • Endogenous ALK7 ligand in hippocampus not identified
    • Mechanism linking Smad signaling to synaptic plasticity genes undefined
  14. 2025 Medium

    In pancreatic cancer, ALK7 was shown to drive metastasis through non-canonical β-catenin–EMT and β-catenin–MMP pathways promoting intravasation, redefining ALK7 as context-dependently pro-metastatic rather than purely tumor-suppressive.

    Evidence Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic and pharmacological ALK7 inhibition, β-catenin/MMP pathway analysis

    PMID:40616087

    Open questions at the time
    • Single-lab study; non-canonical β-catenin pathway not validated independently
    • How ALK7 switches from canonical Smad to non-canonical β-catenin signaling unknown
    • Therapeutic window for ALK7 inhibition in cancer vs metabolic disease unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the structural basis of ALK7 ligand selectivity and co-receptor requirement, (2) the molecular switch between canonical Smad and non-canonical (β-catenin, ERK) pathway engagement, (3) whether ALK7 can be selectively targeted therapeutically given shared inhibitor sensitivity with ALK4/ALK5, and (4) the identity and role of ALK7 ligands in the CNS.
  • No crystal structure of ALK7 with any ligand
  • No ALK7-selective small molecule inhibitor reported
  • CNS ligand identity unknown
  • Patient stratification criteria for ALK7-targeted therapy undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2
Partners
ACVR2AACVR2BINHBBINHBENODALSMAD2SMAD3TDGF1
Complex memberships
ALK7/ActRIIAALK7/ActRIIB

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ALK7 (ACVR1C) acts as a type I receptor for Nodal proteins, collaborating with ActRIIB to confer responsiveness to Xnr1 and Nodal; both receptors independently bind Xnr1. Cripto can independently interact with both Xnr1 and ALK7 and greatly enhances ALK7/ActRIIB responsiveness to Nodal. A constitutively active ALK7 mimics mesendoderm-inducing activity of Xnr1, while dominant-negative ALK7 specifically blocks Nodal and Xnr1 activities. Receptor reconstitution experiments, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays Genes & development High 11485994
2002 SB-431542 selectively inhibits the kinase activity of ALK4, ALK5, and ALK7 (but not other ALK family members), blocking endogenous activin, TGF-beta, and Nodal signaling without affecting BMP signaling or ERK/JNK/p38 MAP kinase pathways. In vitro kinase assay, cell-based signaling assays with selective ALK inhibitor Molecular pharmacology High 12065756
1999 Constitutively active ALK7 (T194D) activates Smad2 and Smad3, translocating them to the nucleus and inducing PAI-1 promoter activity. The MH1 domain of Smad2 has an inhibitory effect on nuclear localization, while the MH1 domain of Smad3 is required for full activation downstream of ALK7. Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assay, PAI-1 promoter-reporter assay Biochemical and biophysical research communications Medium 9920806
2000 Constitutively active ALK7 activates Smad2 and Smad3 (but not Smad1), ERK, and JNK signaling; induces Smad7, c-fos, and PAI-1 expression; inhibits proliferation via upregulation of p15INK4B and p21; and drives morphological differentiation with actin rearrangement in PC12 cells. Tetracycline-inducible constitutively active ALK7 expression in PC12 cells, thymidine incorporation, reporter assays, Western blotting The Journal of biological chemistry High 11084022
2001 Human ALK7 (ACVR1C) gene maps to chromosome 2q24.1→q3; constitutively active ALK7 (Ad-caALK7) infection of MIN6 insulinoma cells induces marked phosphorylation of Smad2, confirming functional ALK7 signaling in pancreatic beta cells. FISH mapping, recombinant adenovirus infection, Western blot for pSmad2 Cytogenetics and cell genetics Medium 12063393
2002 Alternative splicing of the human ALK7 gene produces four protein variants: full-length ALK7, truncated ALK7 (tALK7, lacking first 50 amino acids of ligand-binding domain), and two soluble forms (sALK7a, sALK7b) lacking transmembrane and GS domains. All isoforms are expressed in human placenta in a developmentally regulated manner. PCR cloning, Western blot, RT-PCR, exon mapping Biology of reproduction Medium 12606401
2004 Nodal, acting through ALK7 and Smad2/3, inhibits proliferation and induces apoptosis in human trophoblast cells. Constitutively active ALK7 mimics Nodal effects; kinase-deficient ALK7 blocks them. Nodal/ALK7 induces G1 arrest by increasing p27 and decreasing Cdk2 and cyclin D1. Overexpression of Nodal and constitutively active/kinase-deficient ALK7, dominant-negative Smad2/3, BrdU proliferation assay, flow cytometry, caspase-3 Western blot, Hoechst staining The Journal of biological chemistry High 15150278
2004 Activin AB and activin B are ligands for ALK7; the combination of ActRIIA and ALK7 (preferred by activin AB and activin B, but not activin A) mediates activin-induced insulin secretion from MIN6 beta cells. Activin A signals preferentially through ActRIIA/ALK4. Receptor reconstitution in cell lines, insulin secretion assay Molecular and cellular endocrinology High 15196700
2004 ALK7 knockout mice develop normally with no left-right patterning defects, demonstrating that ALK7 is dispensable for Nodal-mediated mesendoderm formation and left-right patterning in the mouse but may have tissue-specific roles in metabolic and neurological function. ALK7 knockout mouse generation and characterization, histological analysis, compound mutant analysis Molecular and cellular biology High 15485907
2004 SB-505124 selectively inhibits ALK4-, ALK5-, and ALK7-dependent Smad2/3 activation without affecting ALK1, ALK2, ALK3, or ALK6 signaling, and blocks TGF-beta-induced MAPK activation and cell death. Cell-based Smad2/3 phosphorylation assay, selective ALK inhibitor characterization Molecular pharmacology High 14978253
2006 ALK7 can mediate activin B signaling in gonadotrope cells to stimulate FSHbeta transcription through Smad3; constitutively active ALK7 and ALK4 both stimulate Smad2/3 phosphorylation and Fshb promoter activity, effects that are blocked by Smad3 depletion. Constitutively active and kinase-deficient ALK receptor transfection, Fshb promoter-reporter assay, shRNA Smad3 knockdown, RT-PCR, Western blot Reproductive biology and endocrinology Medium 17040568
2008 ALK7 negatively regulates glucose-stimulated insulin secretion in pancreatic beta cells through mediating activin B effects on Ca2+ signaling; ALK7 and activin B function in a common pathway, as double knockouts show no additive hyperinsulinemia. Activin A and activin B have opposing effects on Ca2+ influx. ALK7 and activin B knockout mice, calcium imaging, insulin secretion assay, double mutant epistasis analysis Proceedings of the National Academy of Sciences of the United States of America High 18480258
2008 GDF3 signals through ALK7 (and co-receptor Cripto) in adipose tissue to regulate adipose accumulation; Gdf3-/- and Alk7-/- mice both show reduced fat mass and partial resistance to high-fat diet-induced obesity. Knockout mouse phenotyping, high-fat diet challenge, ligand-receptor signaling assays Proceedings of the National Academy of Sciences of the United States of America High 18480258 18480259
2012 Nodal activates ALK7 signaling to induce apoptosis in pancreatic beta cells through Smad2/3-caspase-3 activation and suppression of Akt/XIAP; siRNA-mediated ALK7 knockdown significantly attenuates Nodal-induced apoptosis. siRNA knockdown of ALK7, Nodal overexpression, caspase-3 assay, Akt phosphorylation Western blot, XIAP expression analysis, constitutively active Akt rescue American journal of physiology. Endocrinology and metabolism High 22550067
2012 ALK7 is expressed in SF1-positive granulosa cells, FSH gonadotrophs, and NPY-expressing arcuate neurons; Alk7 knockout females show delayed puberty, abnormal estrous cyclicity, premature follicle depletion, impaired gonadotropin responses, and reduced NPY/AgRP innervation to medial preoptic area. Alk7 knockout mouse characterization, immunohistochemistry, hormone measurements, NPY/AgRP circuit analysis FASEB journal High 22954591
2014 ALK7 mediates diet-induced catecholamine resistance in adipose tissue; fat-specific Alk7 knockout enhances adipose beta-adrenergic receptor expression, beta-adrenergic signaling, mitochondrial biogenesis, lipolysis, and energy expenditure, reducing obesity. Acute chemical-genetic ALK7 inhibition recapitulates these effects. ALK7 activation reduces beta-AR-mediated signaling and lipolysis cell-autonomously in mouse and human adipocytes. Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, beta-adrenergic signaling assays, lipolysis assays, energy expenditure measurement, human adipocyte experiments eLife High 25161195
2015 ALK7 protects against pathological cardiac hypertrophy; ALK7 disruption aggravates cardiac hypertrophy and fibrosis while cardiac-specific ALK7 overexpression is protective. Mechanistically, ALK7-dependent cardioprotection operates through inhibition of the MEK-ERK1/2 signaling pathway. ALK7 knockout and cardiac-specific transgenic mice, aortic banding model, echocardiography, in vitro cardiomyocyte assays, MEK-ERK1/2 pathway analysis Cardiovascular research Medium 26249805
2015 Nodal fragments encompassing the pre-helix loop and H3 helix (residues 44-67) bind directly to recombinant ALK7 and ALK4 in vitro by surface plasmon resonance; residue Y58 of Nodal is implicated in recognition by both ALK7 and the co-receptor Cripto. Surface plasmon resonance binding assays, NMR/CD structural characterization, site-directed mutagenesis of Nodal peptides Journal of peptide science Medium 25588905
2015 ALK7 is upregulated by cGMP/PKG signaling during brown adipocyte differentiation; activin AB activates ALK7-SMAD3 signaling in brown preadipocytes to suppress PPARgamma and differentiation, while ALK7 activation during late differentiation reduces lipid content but enhances UCP1 expression. Pharmacological and genetic tools in murine brown adipocytes, differentiation assays, SMAD3 signaling analysis, cGMP pathway modulation Molecular metabolism Medium 26266090
2016 ALK7 maintains cardiac repolarization by supporting expression of repolarizing K+ channels; Alk7-/- cardiomyocytes show reduced Ito and IK1 currents, decreased Kv4.2 and KCHIP2 expression, prolonged action potential duration, and increased ventricular arrhythmia susceptibility. Alk7 knockout mice, telemetry ECG, Langendorff perfusion, whole-cell patch clamp, Western blot PloS one Medium 26882027
2018 ACVR1C/ALK7 signaling through SMAD2 (not SMAD3) promotes invasion, growth, and survival of retinoblastoma cells; pharmacological inhibition with SB505124 or shRNA knockdown suppresses invasion and reduces ZEB1/Snail mesenchymal markers. ALK7 knockdown reduces tumor spread in an orthotopic zebrafish model. shRNA knockdown, pharmacological inhibition, invasion assays, apoptosis assays, zebrafish orthotopic model, Western blot Oncogene High 30401983
2019 ALK7 activated by activin B induces apoptosis in neoplastic cells, acting as a tumor suppressor barrier; during tumorigenesis, cancer cells evade this by downregulating activin B and/or ALK7. Suppression of ALK7 enhances metastatic seeding in mouse models of pancreatic neuroendocrine and luminal breast cancer. Functional studies in mouse cancer models, experimental metastasis assays, ALK7 expression modulation Developmental cell High 31063757
2019 The activin-ALK7 pathway mediates endothelial ablation by pancreatic ductal adenocarcinoma; PDAC cells use ALK7 signaling to destroy endothelial cells in a 3D organotypic tumor-on-a-chip model and in vivo PDAC models, contributing to tumor hypovascularity. 3D organotypic PDAC-on-a-chip model, in vivo PDAC models, pharmacological inhibition of ALK7 Science advances Medium 31489365
2020 ALK7 in brown adipose tissue limits catabolic responses to nutrient stress; BAT-specific ALK7 deletion causes fasting-induced hypothermia due to exaggerated catabolism, with increased KLF15, proline dehydrogenase (POX), and ATGL expression. ALK7 ligand stimulation suppresses POX and KLF15 in brown adipocytes. Glucocorticoid receptor antagonist (RU486) normalizes KLF15/POX in mutant BAT, implicating excessive glucocorticoid signaling. BAT-specific Alk7 conditional knockout, fasting/cold challenge, gene expression analysis, ligand stimulation of human brown adipocytes, RU486 pharmacological rescue eLife High 32366358
2021 Activin E (INHBE) signals through ACVR1C to suppress beta-agonist-induced lipolysis in adipose tissue, activating SMAD2/3 signaling and suppressing PPARgamma target genes; loss of activin E or ACVR1C increases fat utilization and drives PPARgamma-regulated gene signatures indicative of healthy adipose function. Activin E and ACVR1C knockout mice, SMAD2/3 signaling assay, lipolysis assay, RNA-seq, ligand-receptor identification Proceedings of the National Academy of Sciences of the United States of America High 37523551
2021 Conditional ALK7 ablation in adipocytes synergizes with low-fat diet switch or anti-inflammatory treatment (Na-salicylate) to enhance lipolysis and energy expenditure; mechanistically, this combination strongly upregulates beta3-AR expression and its upstream regulator C/EBPalpha. Conditional adipocyte-specific Alk7 knockout in obese mice, pharmacological treatment, beta3-AR/C/EBPalpha expression analysis FASEB journal Medium 34245608
2021 ACVR1C signaling through SMAD2 phosphorylation regulates SREBP1 and ACC expression in keratinocytes; UV irradiation decreases ACVR1C and epidermal triglyceride synthesis, effects modulated by ACVR1C knockdown or overexpression. shRNA knockdown and overexpression, UV irradiation, Western blot for pSMAD2, lipogenic gene expression analysis International journal of molecular sciences Medium 33499275
2024 Human ACVR1C missense variants (I195T, I482V, N150H) have graded effects on ALK7 signaling and metabolic phenotype in knock-in mice: I195T phenocopies null mutants (impaired ALK7 signaling, HFD-obesity resistance, enhanced lipolysis); I482V shows partial phenotype; N150H is metabolically indistinguishable from wild type at normal ligand concentrations but shows reduced signaling at low ligand levels. Knock-in mouse models for each human variant, high-fat diet challenge, ALK7 signaling assays, lipolysis assays, fat mass measurement Molecular metabolism High 38307384
2024 ACVR1C expression is epigenetically regulated at its promoter by exercise (alleviating repression); ACVR1C activation suppresses Mkrn3 via Smad2/3 signaling, involving KAP1 recruitment and repressive histone modifications. ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice; overexpression of Acvr1c enables learning in aged/5xFAD mice. RNA-seq of dorsal hippocampus, epigenetic analysis (ChIP), Acvr1c overexpression in mice, synaptic plasticity assays, memory behavior tests Nature communications Medium 38714691
2025 Acvr1c activation suppresses Mkrn3 expression via Smad2/3 signaling with KAP1 recruitment and repressive histone modifications at the Mkrn3 locus, providing a mechanism for pubertal timing regulation. RNA-seq correlation analysis, experimental validation of Acvr1c activation, ChIP for KAP1 and histone marks, Smad2/3 signaling assays NAR molecular medicine Medium 41255711
2025 In pancreatic cancer, ALK7 drives metastasis through two non-canonical pathways: ALK7-beta-catenin-EMT (enhancing tumor cell motility) and ALK7-beta-catenin-MMP (upregulating MMPs, ECM degradation, invadosome formation, vascular basement membrane breakdown, and intravasation). Both pharmacological and genetic ALK7 inhibition suppress metastasis in orthotopic models and 3D microfluidic vessel-on-chip platforms. Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic knockdown/knockout, pharmacological inhibition, MMP inhibition, beta-catenin pathway analysis Molecular cancer Medium 40616087
2025 GREM1 binds ACVR1C as a novel high-affinity epithelial receptor, activating SMAD2/3 signaling which upregulates SNAI1 and GREM1 itself, establishing a positive feedback autocrine loop that sustains EMT and promotes colorectal cancer metastasis. Binding assays identifying ACVR1C as GREM1 receptor, SMAD2/3 signaling assays, in vivo metastasis models, feedback loop characterization bioRxivpreprint Medium

Source papers

Stage 0 corpus · 54 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
2001 The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes & development 261 11485994
2019 A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling. Science advances 138 31489365
2004 Activin isoforms signal through type I receptor serine/threonine kinase ALK7. Molecular and cellular endocrinology 121 15196700
2008 Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America 106 18480259
2004 Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. The Journal of biological chemistry 97 15150278
2008 Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proceedings of the National Academy of Sciences of the United States of America 81 18480258
2014 Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity. eLife 67 25161195
2009 ALK7 expression is specific for adipose tissue, reduced in obesity and correlates to factors implicated in metabolic disease. Biochemical and biophysical research communications 64 19275893
2006 Activin B can signal through both ALK4 and ALK7 in gonadotrope cells. Reproductive biology and endocrinology : RB&E 62 17040568
2000 The orphan receptor serine/threonine kinase ALK7 signals arrest of proliferation and morphological differentiation in a neuronal cell line. The Journal of biological chemistry 48 11084022
2018 ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma. Oncogene 41 30401983
2004 ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in the mouse. Molecular and cellular biology 40 15485907
2019 ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis. Developmental cell 39 31063757
2001 cDNA cloning, expression studies and chromosome mapping of human type I serine/threonine kinase receptor ALK7 (ACVR1C). Cytogenetics and cell genetics 39 12063393
2006 Activation and roles of ALK4/ALK7-mediated maternal TGFbeta signals in zebrafish embryo. Biochemical and biophysical research communications 38 16696945
2002 Identification of novel isoforms of activin receptor-like kinase 7 (ALK7) generated by alternative splicing and expression of ALK7 and its ligand, Nodal, in human placenta. Biology of reproduction 34 12606401
2018 DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes. Diabetes 33 30389748
1999 The MH1 domains of smad2 and smad3 are involved in the regulation of the ALK7 signals. Biochemical and biophysical research communications 33 9920806
2023 Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proceedings of the National Academy of Sciences of the United States of America 30 37523551
2018 MicroRNA-454 contributes to sustaining the proliferation and invasion of trophoblast cells through inhibiting Nodal/ALK7 signaling in pre-eclampsia. Chemico-biological interactions 29 30367833
2006 ALK7 is a novel marker for adipocyte differentiation. The journal of medical investigation : JMI 29 16953060
2012 Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 β-cells. American journal of physiology. Endocrinology and metabolism 25 22550067
2012 Neuroendocrine control of female reproductive function by the activin receptor ALK7. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 22954591
2021 Regulation of metabolic homeostasis by the TGF-β superfamily receptor ALK7. The FEBS journal 20 34173336
2015 ALK7 protects against pathological cardiac hypertrophy in mice. Cardiovascular research 19 26249805
2020 Control of brown adipose tissue adaptation to nutrient stress by the activin receptor ALK7. eLife 15 32366358
2013 ALK7 gene polymorphism is associated with metabolic syndrome risk and cardiovascular remodeling. Arquivos brasileiros de cardiologia 15 23765385
2018 ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation. Endocrine-related cancer 13 30012586
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
2024 Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice. Nature communications 11 38714691
2016 Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia. PloS one 11 26882027
2015 A novel crosstalk between Alk7 and cGMP signaling differentially regulates brown adipocyte function. Molecular metabolism 11 26266090
2022 ALK7 Inhibition Protects Osteoblast Cells Against High Glucoseinduced ROS Production via Nrf2/HO-1 Signaling Pathway. Current molecular medicine 9 34126915
2021 Sustained anti-obesity effects of life-style change and anti-inflammatory interventions after conditional inactivation of the activin receptor ALK7. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 34245608
2021 Epstein-Barr virus microRNA BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7. Experimental biology and medicine (Maywood, N.J.) 9 34424090
2019 Knockdown of ALK7 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells. Clinical and experimental pharmacology & physiology 9 31608496
2022 Hypoxia induced-disruption of lncRNA TUG1/PRC2 interaction impairs human trophoblast invasion through epigenetically activating Nodal/ALK7 signalling. Journal of cellular and molecular medicine 8 35729773
2020 ALK7 Acts as a Positive Regulator of Macrophage Activation through Down-Regulation of PPARγ Expression. Journal of atherosclerosis and thrombosis 8 32641645
2025 Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation. Molecular cancer 7 40616087
2024 Human ACVR1C missense variants that correlate with altered body fat distribution produce metabolic alterations of graded severity in knock-in mutant mice. Molecular metabolism 6 38307384
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
2020 ALK7 Promotes Vascular Smooth Muscle Cells Phenotypic Modulation by Negative Regulating PPARγ Expression. Journal of cardiovascular pharmacology 5 32467530
2021 UV-Induced Reduction of ACVR1C Decreases SREBP1 and ACC Expression by the Suppression of SMAD2 Phosphorylation in Normal Human Epidermal Keratinocytes. International journal of molecular sciences 4 33499275
2019 ALK7 Erects a Suppressive Barrier to Tumor Progression and Metastasis. Developmental cell 4 31063746
2023 The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes? Endocrine journal 2 37081691
2022 The Photoperiod Regulates Granulosa Cell Apoptosis through the FSH-Nodal/ALK7 Signaling Pathway in Phodopus sungorus. Animals : an open access journal from MDPI 2 36552491
2015 Fibrodysplasia ossificans progressiva with minor unilateral hallux anomaly in a sporadic case from Northern Tanzania with the common ACVR1c.617G>A mutation. The Pan African medical journal 2 26966495
2022 ALK7 Knockdown Plays a Protective Role on HG-Stimulated MCs through Activation of the Nrf2/HO-1 Pathway. Disease markers 1 36199821
2025 MEIS1‑regulated miR‑488‑3p suppresses the malignant progression of laryngeal squamous cell carcinoma by targeting ACVR1C. International journal of molecular medicine 0 40682848
2025 Protocatechuic aldehyde promotes diabetic wound healing by enhancing angiogenesis via H3K18 lactylation-mediated Acvr1c expression. Molecular immunology 0 41033083
2025 High-throughput transcriptome analysis reveals a developmental increase in Acvr1c which mediates epigenetic repression of the gene encoding the pubertal brake, Makorin ring finger protein 3. NAR molecular medicine 0 41255711
2023 Retracted: ALK7 Knockdown Plays a Protective Role on HG-Stimulated MCs through Activation of the Nrf2/HO-1 Pathway. Disease markers 0 38077937