Affinage

ACVR1C

Activin receptor type-1C · UniProt Q8NER5

Length
493 aa
Mass
54.9 kDa
Annotated
2026-06-09
54 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

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, together with type II receptors (ActRIIB/ActRIIA) and the co-receptor Cripto, transduces signals from Nodal and the activins to phosphorylate Smad2 and Smad3 and drive their nuclear translocation and transcriptional output (PMID:11485994, PMID:11084022, PMID:9920806). Ligand specificity distinguishes ALK7 within the activin system: activin AB, activin B, GDF3, and activin E (but not activin A) act through ALK7, with ActRIIA+ALK7 the preferred receptor combination, and Nodal binds via a defined pre-helix/H3 interface centered on Y58 (PMID:15196700, PMID:18480259, PMID:37523551, PMID:25588905). ALK7 signaling is antiproliferative and pro-apoptotic in epithelial and endocrine contexts, inducing p27/p15/p21 and G1 arrest and caspase-3 activation while suppressing Akt and XIAP, and serving as a tumor-suppressive barrier in pancreatic neuroendocrine and breast cancer via activin B (PMID:11084022, PMID:15150278, PMID:22550067, PMID:31063757). Its dominant physiological role is metabolic: ALK7 negatively regulates adipocyte lipolysis and β-adrenergic signaling—suppressing β3-AR through C/EBPα—restrains brown-fat catabolism by repressing KLF15/POX/ATGL, limits glucose-stimulated insulin secretion by curbing β-cell Ca2+ influx, and human ACVR1C missense variants produce graded loss of signaling with leanness and enhanced lipolysis (PMID:18480258, PMID:25161195, PMID:32366358, PMID:37523551, PMID:34245608, PMID:38307384). ALK7 additionally gates female pubertal onset and reproductive function through hypothalamic NPY/AgRP circuitry and epigenetic repression of Mkrn3 via Kap1, and bidirectionally regulates hippocampal synaptic plasticity and memory (PMID:22954591, PMID:38714691, PMID:41255711). In cancer it can also act non-canonically and pro-metastatically through β-catenin–EMT/MMP axes and a GREM1 autocrine SMAD2/3 loop [PMID:bio_10.1101_2025.07.11.664267, PMID:40616087].

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 High

    Established that ALK7 is a functional Smad-activating kinase receptor, defining its core signaling output before its ligands were known.

    Evidence Constitutively active ALK7 (T194D) transfection with chimeric Smad domain-swap constructs and PAI-1 reporter assays

    PMID:11084022 PMID:9920806

    Open questions at the time
    • Used a constitutively active mutant rather than physiological ligand
    • Smad2 vs Smad3 selectivity of endogenous receptor not resolved
  2. 2001 High

    Identified the receptor architecture: ALK7 partners with type II receptor ActRIIB and co-receptor Cripto to confer Nodal/Xnr1 responsiveness, placing ALK7 in the Nodal pathway.

    Evidence Receptor reconstitution, dominant-negative/constitutively active constructs, and Xenopus embryo functional assays

    PMID:11485994 PMID:12063393

    Open questions at the time
    • Cell-type contexts where ALK7 functions endogenously not defined
    • Quantitative affinities of the receptor-ligand complex not measured
  3. 2002 High

    Provided pharmacological tools (SB-431542, SB-505124) that selectively block ALK4/ALK5/ALK7 kinase activity, enabling specific interrogation of ALK7-dependent Smad2/3 signaling.

    Evidence Small-molecule kinase inhibition with selectivity profiling across ALK family and MAPK pathways

    PMID:12065756 PMID:14978253

    Open questions at the time
    • Inhibitors do not distinguish ALK7 from ALK4/ALK5
    • No ALK7-selective inhibitor identified
  4. 2004 High

    Defined ALK7 ligand specificity (activin AB/B but not activin A) and showed ALK7 is dispensable for embryonic Nodal signaling, redirecting attention to postnatal physiological roles.

    Evidence Receptor isoform-specific ligand-response assays in MIN6 cells and ALK7-knockout/compound-mutant mouse analysis

    PMID:15150278 PMID:15196700 PMID:15485907

    Open questions at the time
    • Why ALK7 is dispensable for early Nodal signaling despite biochemical responsiveness not fully explained
    • Full ligand repertoire still incomplete at this point
  5. 2008 High

    Established ALK7 as a negative regulator of metabolism, linking activin B/GDF3-ALK7 signaling to insulin secretion control and adipose accumulation in vivo.

    Evidence ALK7-, activin B-, and Gdf3-knockout mice with double-mutant epistasis, Ca2+ imaging, and high-fat-diet metabolic phenotyping

    PMID:18480258 PMID:18480259

    Open questions at the time
    • Tissue-autonomous vs systemic contributions not separated
    • Downstream transcriptional effectors of metabolic suppression not yet identified
  6. 2014 High

    Resolved the adipocyte mechanism: ALK7 cell-autonomously suppresses β-adrenergic signaling and lipolysis, identifying it as a brake on catecholamine-driven fat mobilization.

    Evidence Global, fat-specific, and acute chemical-genetic ALK7 inhibition in mice plus mouse and human adipocyte lipolysis assays

    PMID:25161195

    Open questions at the time
    • Molecular link from Smad signaling to β-AR suppression not defined here
    • Endogenous ligand driving adipose ALK7 not pinpointed
  7. 2021 High

    Connected ALK7 to specific molecular effectors of metabolism—C/EBPα-dependent β3-AR repression, PPARγ-regulated gene programs, and brown-fat KLF15/POX/ATGL suppression—and identified activin E as a physiological adipose ligand.

    Evidence Tissue-specific and conditional ALK7 knockouts, activin E knockout, fasting/cold challenge, and downstream gene expression analysis

    PMID:26266090 PMID:32366358 PMID:34245608 PMID:37523551

    Open questions at the time
    • Relative contributions of activin B, GDF3, and activin E in different fat depots unresolved
    • How SMAD2/3 mechanistically controls C/EBPα/PPARγ not fully elaborated
  8. 2024 Medium

    Validated human relevance by showing ACVR1C missense variants cause graded loss of ALK7 signaling and metabolic phenotypes, and revealed a CNS role in synaptic plasticity and memory.

    Evidence Knock-in mouse models of human variants with metabolic phenotyping; hippocampal RNA-seq, overexpression, and 5xFAD memory/plasticity assays

    PMID:38307384 PMID:38714691

    Open questions at the time
    • Human variant signaling threshold differs from mouse, complicating translation
    • Mechanism of bidirectional synaptic regulation not defined
  9. 2025 Medium

    Extended ALK7 mechanism to epigenetic gene control and non-canonical oncogenic signaling, including Kap1-mediated Mkrn3 repression and β-catenin/GREM1-driven metastasis.

    Evidence Acvr1c activation with Kap1 recruitment and histone-modification analysis; GREM1 binding assays and orthotopic CRC/PDAC metastasis models with ALK7 inhibition

    PMID:40616087 PMID:41255711

    Open questions at the time
    • GREM1-ACVR1C interaction reported only in a preprint
    • Switch between tumor-suppressive and pro-metastatic ALK7 output not mechanistically reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines whether ALK7-Smad2/3 signaling is anti-proliferative/tumor-suppressive versus pro-metastatic and non-canonical (β-catenin/MMP) remains unresolved.
  • Context-dependent ligand and co-receptor determinants of output unknown
  • No structural model of the full ALK7 receptor complex with each ligand
  • Canonical Smad vs non-canonical β-catenin pathway branching mechanism undefined

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 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-4839726 Chromatin organization 1
Partners
ACVR2AACVR2BGDF3GREM1INHBBINHBENODALTDGF1

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 serine/threonine kinase receptor for Nodal and Xnr1, collaborating with the type II receptor ActRIIB to confer responsiveness. Both receptors can independently bind Xnr1. Cripto can independently interact with both Xnr1 and ALK7, and greatly enhances ALK7/ActRIIB-mediated Nodal signaling. A constitutively active ALK7 mimics mesendoderm-inducing activity of Xnr1, while dominant-negative ALK7 specifically blocks Nodal/Xnr1 activity. Receptor reconstitution experiments, dominant-negative and constitutively active receptor constructs, Xenopus embryo functional assays, binding assays Genes & development High 11485994
2000 Constitutively active ALK7 (T194D) activates Smad2 and Smad3 (but not Smad1) and MAP kinases ERK and JNK in PC12 neuronal cells. ALK7 activation stimulates transcription from Smad-binding elements (PAI-1, JunB), induces Smad7 and c-fos, causes anti-proliferative effects linked to p15 and p21 induction, and produces morphological differentiation with actin rearrangements distinct from ALK5 signaling. Tetracycline-inducible constitutively active ALK7 in PC12 cell line, Smad phosphorylation assays, reporter assays, thymidine incorporation, Western blot, morphological analysis The Journal of biological chemistry High 11084022
1999 Constitutively active ALK7 (T194D) activates Smad3 and translocates it to the nucleus, inducing PAI-1 promoter activation. The MH1 domain of Smad2 has inhibitory effects on nuclear localization downstream of ALK7; chimeric Smad3-2 (MH1 of Smad3, MH2 of Smad2) is activated, but Smad2-3 (MH1 of Smad2, MH2 of Smad3) is not. Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assays, PAI-1 reporter assay Biochemical and biophysical research communications Medium 9920806
2001 Human ALK7 (ACVR1C) gene maps to chromosome 2q24.1→q3. The constitutively active ALK7 adenovirus (Ad-caALK7) markedly increases Smad2 phosphorylation in MIN6 insulinoma cells in a ligand-independent manner, confirming functional downstream signaling. FISH chromosomal mapping, recombinant adenovirus infection, Western blot for phospho-Smad2 Cytogenetics and cell genetics Medium 12063393
2002 SB-431542 inhibits the kinase activity of ALK4, ALK5, and ALK7 (but not other ALK family members recognizing BMPs), selectively blocking activin and TGF-β signaling without affecting BMP, ERK, JNK, or p38 MAP kinase pathways. Small molecule kinase inhibition assays, selective pathway readouts, signaling reporter assays Molecular pharmacology High 12065756
2004 SB-505124 selectively inhibits ALK4-, ALK5-, and ALK7-dependent activation of Smad2 and Smad3 and TGF-β-induced MAPK components, without altering ALK1, ALK2, ALK3, or ALK6-induced Smad signaling. It is 3-5x more potent than SB-431542. Selective kinase inhibition assays, Smad2/3 phosphorylation readouts, cell death assays Molecular pharmacology High 14978253
2004 Activin AB and activin B (but not activin A) are ligands for ALK7. The preferred receptor combination is ActRIIA + ALK7 for activin AB and activin B, which mediates insulin secretion from pancreatic MIN6 beta cells. All activins can activate ActRIIA + ALK4 with varying potency. Receptor signaling assays, insulin secretion assays in MIN6 cells, receptor isoform-specific ligand-response experiments Molecular and cellular endocrinology High 15196700
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. ALK7/Nodal signaling increases p27 and reduces Cdk2 and cyclin D1, causing G1 cell cycle arrest via the p27-cyclin E/Cdk2 pathway. Overexpression of Nodal and constitutively active/kinase-deficient ALK7, dominant-negative Smad2/3, Hoechst staining, flow cytometry, caspase-3 Western blot, BrdU assays, Western blot for cell cycle proteins The Journal of biological chemistry High 15150278
2004 ALK7-knockout mice are viable and fertile with no embryonic lethality, mesendoderm formation defects, or left-right patterning abnormalities, demonstrating that ALK7 is not an essential mediator of Nodal signaling during gastrulation in the mouse, in contrast to ALK4. Generation and analysis of ALK7-knockout mice, compound mutant analysis (ALK7−/−; Nodal+/− and ALK7−/−; ALK4+/−) Molecular and cellular biology High 15485907
2006 ALK7 is expressed in gonadotrope (LβT2) cells and selectively potentiates activin B (but not activin A) stimulation of FSHβ promoter activity. Constitutively active ALK7 (TD) stimulates endogenous Fshb mRNA and phosphorylates Smad2/3; these effects require endogenous Smad3. RT-PCR, transfection of wild-type/kinase-deficient/constitutively active ALK7 and ALK4, promoter-reporter assays, Western blot for phospho-Smad2/3, shRNA-mediated Smad3 depletion Reproductive biology and endocrinology Medium 17040568
2008 ALK7-knockout mice develop age-dependent hyperinsulinemia, reduced insulin sensitivity, liver steatosis, and impaired glucose tolerance. ALK7-null islets show enhanced glucose-stimulated insulin secretion, indicating ALK7 negatively regulates insulin release. Activin B (signaling through ALK7) decreases glucose-stimulated Ca2+ influx in beta cells, while activin A (not signaling through ALK7) increases it. Double mutants (ALK7−/−; activin B−/−) show no additive effects, placing activin B and ALK7 in a common pathway for insulin secretion regulation. ALK7-knockout mouse model, activin B knockout, double mutant analysis, in vivo metabolic phenotyping, Ca2+ imaging in islet cells, insulin secretion assays Proceedings of the National Academy of Sciences of the United States of America High 18480258
2008 GDF3 signals through ALK7 and its coreceptor Cripto (both expressed in adipose tissue) to regulate adipose tissue accumulation. ALK7-knockout mice show reduced fat accumulation and partial resistance to high-fat diet-induced obesity, phenocopying Gdf3-knockout mice. Knockout mouse models (Gdf3−/−, ALK7−/−), high-fat diet challenge, adipose tissue analysis, receptor signaling experiments Proceedings of the National Academy of Sciences of the United States of America High 18480259
2012 Nodal activates ALK7 signaling to induce apoptosis in INS-1 pancreatic beta cells through activation of Smad2/3-caspase-3 and suppression of Akt and XIAP. siRNA-mediated ALK7 knockdown attenuates Nodal-induced apoptosis. High glucose, palmitate, or cytokines upregulate Nodal and ALK7 expression and enhance Smad3 phosphorylation. siRNA knockdown, Nodal overexpression, constitutively active Akt/XIAP overexpression, Smad2/3 ablation, caspase-3 Western blot, phospho-Akt assays in INS-1 cells American journal of physiology. Endocrinology and metabolism Medium 22550067
2012 ALK7 is expressed in SF1+ granulosa cells of the ovary, FSH gonadotrophs in the pituitary, and NPY-expressing neurons in the arcuate nucleus of the hypothalamus. ALK7-knockout females show delayed puberty, abnormal estrous cyclicity, premature follicle depletion, and selective loss of arcuate NPY/AgRP innervation in the medial preoptic area, establishing ALK7 as a regulator of female reproductive function through hypothalamic circuitry. ALK7-knockout mouse model, immunofluorescence, in situ hybridization, hormonal assays, histological analysis of ovary/pituitary/hypothalamus, tracttracing FASEB journal High 22954591
2014 Targeted disruption of ALK7 in adipose tissue (global and fat-specific knockout) alleviates diet-induced catecholamine resistance by enhancing β-adrenoreceptor (β-AR) expression, β-adrenergic signaling, mitochondrial biogenesis, lipid oxidation, and lipolysis. Acute chemical-genetic inhibition of ALK7 in adult mice reduces diet-induced weight gain and enhances adipocyte lipolysis. ALK7 activation reduces β-AR-mediated signaling cell-autonomously in both mouse and human adipocytes. Global and fat-specific Alk7 knockout mice, chemical-genetic acute inhibition, high-fat diet challenge, β-AR signaling assays, energy expenditure measurements, lipolysis assays in mouse and human adipocytes eLife High 25161195
2015 ALK7-dependent cardioprotection against pressure overload-induced hypertrophy is mediated through inhibition of the MEK-ERK1/2 signaling pathway. ALK7-knockout mice show aggravated hypertrophy with increased fibrosis; cardiac-specific ALK7-transgenic mice show the opposite phenotype. ALK7 also protects against angiotensin II-induced cardiomyocyte hypertrophy in vitro. ALK7-knockout mice, cardiac-specific ALK7-transgenic mice, aortic banding, echocardiography, MEK-ERK1/2 pathway analysis, in vitro cardiomyocyte assays Cardiovascular research Medium 26249805
2015 ALK7 loss in ventricular cardiomyocytes reduces density of repolarizing K+ currents Ito and IK1 and decreases expression of Kv4.2 and KCHIP2 (Ito channel subunits), leading to prolonged action potential duration and ventricular arrhythmia susceptibility in ALK7-knockout mice. ALK7-knockout mice, telemetry ECG, Langendorff heart perfusion, whole-cell patch clamp, Western blot PloS one Medium 26882027
2018 ACVR1C/ALK7 promotes invasion and growth of retinoblastoma via SMAD2 (but not SMAD3) signaling, increasing mesenchymal marker ZEB1 and Snail expression. Pharmacological inhibition (SB505124) or shRNA knockdown of ACVR1C suppresses invasion, growth, and survival in vitro, and reduces tumor spread in an orthotopic zebrafish model. shRNA knockdown, pharmacological inhibition (SB505124), SMAD2/3 knockdown, invasion/proliferation assays, Western blot, orthotopic zebrafish tumor model Oncogene High 30401983
2019 ALK7 activation by its ligand activin B induces apoptosis in neoplastic cells during tumorigenesis in mouse models of pancreatic neuroendocrine and luminal breast cancer, acting as a tumor-suppressive barrier. Cancer cells evade this barrier by downregulating activin B and/or ALK7. Mouse tumor models (RIP-Tag pancreatic neuroendocrine, luminal breast cancer), experimental metastasis assays, genetic manipulation of ALK7/activin B expression Developmental cell High 31063757
2019 The activin-ALK7 signaling pathway mediates endothelial ablation by pancreatic ductal adenocarcinoma cells. In a 3D organ-on-chip model, PDAC cells invade through matrix, enter vessel lumen, and ablate endothelial cells; this process was confirmed in in vivo PDAC models. Organotypic PDAC-on-a-chip 3D culture model, in vivo PDAC mouse models, pathway manipulation assays Science advances Medium 31489365
2020 Specific deletion of ALK7 in brown adipose tissue (BAT) results in fasting-induced hypothermia due to exaggerated catabolic activity. Loss of BAT ALK7 increases KLF15, proline dehydrogenase (POX), and adipose triglyceride lipase (ATGL) expression. ALK7 ligand stimulation suppresses POX and KLF15 in brown adipocytes. Loss of BAT ALK7 results in excessive glucocorticoid signaling activation upon fasting (reversed by glucocorticoid receptor antagonist RU486). BAT-specific ALK7-knockout mice, fasting/cold exposure challenge, gene expression analysis, ligand stimulation assays in mouse and human brown adipocytes, glucocorticoid receptor antagonist treatment eLife High 32366358
2021 Activin E (encoded by INHBE) signals through ACVR1C to activate SMAD2/3 signaling in adipose tissue, suppressing β-agonist-induced lipolysis and promoting fat accumulation. Loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures. ACVR1C loss suppresses PPARG target genes. Activin E and ACVR1C knockout mouse models, SMAD2/3 signaling assays, lipolysis assays, gene expression analysis (PPARG targets) Proceedings of the National Academy of Sciences of the United States of America High 37523551
2021 Conditional ALK7 ablation in adipocytes synergizes with transient low-fat diet or salicylate anti-inflammatory treatment to enhance lipolysis and reduce adipose mass. Mechanistically, the combination strongly enhances β3-AR and C/EBPα levels, linking ALK7 signaling to suppression of β3-AR expression via a C/EBPα-dependent mechanism. Conditional (inducible) adipocyte-specific ALK7 knockout in adult obese mice, high-fat diet, low-fat diet switch, salicylate treatment, lipolysis assays, β3-AR/C/EBPα Western blot FASEB journal Medium 34245608
2021 ACVR1C knockdown in UV-irradiated normal human epidermal keratinocytes decreases SREBP1 and ACC expression, while ACVR1C overexpression attenuates UV-induced decreases in these lipogenic genes. SMAD2 phosphorylation mediates ACVR1C-induced lipogenic gene regulation. shRNA knockdown, overexpression, UV irradiation of NHEK cells, Western blot for SMAD2 phosphorylation and lipogenic genes International journal of molecular sciences Medium 33499275
2024 Human missense variants in ACVR1C (I195T, I482V, N150H) produce graded loss of ALK7 signaling function. Mice with I195T phenocopy null mutants (resistance to HFD obesity, enhanced lipolysis, impaired ALK7 signaling). Mice with I482V show partial resistance and reduced subcutaneous fat. N150H mice are metabolically indistinguishable from wild-type under HFD despite reduced ALK7 signaling at low ligand concentrations, suggesting a lower threshold for ALK7 function in humans than mice. Knock-in mouse models carrying human ACVR1C missense variants, high-fat diet challenge, metabolic phenotyping, lipolysis assays, ALK7 signaling assays Molecular metabolism High 38307384
2024 ACVR1C is a bidirectional regulator of synaptic plasticity and long-term memory in mice. Exercise alleviates epigenetic repression at the Acvr1c promoter during memory consolidation. Overexpression of Acvr1c enables learning and facilitates plasticity in aged mice and in the 5xFAD Alzheimer's model. RNA-seq on dorsal hippocampus, overexpression in mice, 5xFAD mouse model, synaptic plasticity measurements, memory behavioral assays Nature communications Medium 38714691
2025 ACVR1C activation by SMAD2/3 signaling suppresses Mkrn3 expression through recruitment of Kap1 and repressive histone modifications, providing a mechanism for the pre-pubertal decline in MKRN3 that gates pubertal onset. Bioinformatic correlation of Acvr1c with Mkrn3 in developmental RNA-seq datasets, experimental activation of Acvr1c, SMAD2/3 pathway analysis, Kap1 recruitment assays, histone modification analysis NAR molecular medicine Medium 41255711
2025 ACVR1C is a novel high-affinity epithelial receptor for GREM1. Their interaction activates SMAD2/3 signaling, which upregulates SNAI1 and GREM1, establishing a feedback loop that amplifies EMT and promotes colorectal cancer metastasis in vivo. ALK7 inhibition impairs CRC metastasis. Binding assays (GREM1-ACVR1C interaction), SMAD2/3 signaling assays, SNAI1/GREM1 expression analysis, shRNA/pharmacological inhibition, orthotopic in vivo metastasis model bioRxivpreprint Medium bio_10.1101_2025.07.11.664267
2025 ACVR1C promotes pancreatic cancer metastasis through two non-canonical, β-catenin-dependent pathways: (1) ALK7-β-catenin-EMT axis enhancing tumor cell motility; (2) ALK7-β-catenin-MMP axis upregulating MMP production, degrading ECM, promoting invadosome formation, and facilitating basement membrane breakdown and intravasation. Pharmacological and genetic ALK7 inhibition suppresses metastasis in orthotopic and 3D microfluidic models. Orthotopic PDAC metastasis mouse model, 3D microfluidic vessel-on-chip, pharmacological and genetic ALK7 inhibition, β-catenin and MMP pathway analysis, invadosome formation assays Molecular cancer Medium 40616087
2015 Nodal fragments (residues 44–67 covering the pre-helix loop and H3 helix) bind ALK7 and ALK4 in vitro. Y58 of Nodal is implicated in recognition by ALK7 and ALK4, and in binding to Cripto (confirmed by surface plasmon resonance with recombinant proteins). Surface plasmon resonance binding assays, CD and NMR conformational analysis, synthetic peptide mutagenesis Journal of peptide science Medium 25588905
2015 In brown preadipocytes, ALK7 activation by activin AB suppresses PPARγ and inhibits differentiation. Stimulation of ALK7 during late differentiation of brown adipocytes reduces lipid content and adipogenic markers but enhances UCP1 expression. ALK7 expression is increased by cGMP/PKG signaling. Pharmacological and genetic ALK7 manipulation in murine brown adipocytes, differentiation assays, SMAD3 signaling readouts, cGMP/PKG pathway analysis Molecular metabolism Medium 26266090
2020 ALK7 knockdown in macrophages attenuates pro-inflammatory marker expression, decreases foam cell formation, and upregulates PPARγ expression. PPARγ upregulation is required for the anti-inflammatory effect of ALK7 silencing, placing PPARγ downstream of ALK7 in macrophage activation. AdshALK7 knockdown in bone marrow-derived macrophages and peritoneal macrophages, PPARγ inhibitor (G3335), Oil Red O staining, RT-PCR, Western blot Journal of atherosclerosis and thrombosis Medium 32641645

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 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
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 139 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 107 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 82 18480258
2014 Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity. eLife 68 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
2018 DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes. Diabetes 34 30389748
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
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 32 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
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 12 38714691
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
2021 Epstein-Barr virus microRNA BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7. Experimental biology and medicine (Maywood, N.J.) 11 34424090
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
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 10 34245608
2019 Knockdown of ALK7 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells. Clinical and experimental pharmacology & physiology 10 31608496
2022 ALK7 Inhibition Protects Osteoblast Cells Against High Glucoseinduced ROS Production via Nrf2/HO-1 Signaling Pathway. Current molecular medicine 9 34126915
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 9 35729773
2025 Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation. Molecular cancer 8 40616087
2020 ALK7 Acts as a Positive Regulator of Macrophage Activation through Down-Regulation of PPARγ Expression. Journal of atherosclerosis and thrombosis 8 32641645
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 7 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 6 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

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