{"gene":"ACVR1C","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2001,"finding":"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.","method":"Receptor reconstitution experiments, dominant-negative and constitutively active receptor constructs, Xenopus embryo functional assays, binding assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution experiments with multiple orthogonal methods (binding assays, dominant-negative, constitutively active mutants, in vivo embryo assays), replicated across multiple ligands and conditions in a single rigorous study","pmids":["11485994"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Tetracycline-inducible constitutively active ALK7 in PC12 cell line, Smad phosphorylation assays, reporter assays, thymidine incorporation, Western blot, morphological analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — constitutively active mutant with multiple orthogonal readouts (signaling, transcription, proliferation, morphology) in a single controlled study","pmids":["11084022"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assays, PAI-1 reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric Smad domain-swap constructs provide orthogonal mechanistic insight; single lab but multiple constructs tested","pmids":["9920806"],"is_preprint":false},{"year":2001,"finding":"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.","method":"FISH chromosomal mapping, recombinant adenovirus infection, Western blot for phospho-Smad2","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional validation by constitutively active construct plus chromosomal mapping; single lab","pmids":["12063393"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Small molecule kinase inhibition assays, selective pathway readouts, signaling reporter assays","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct kinase inhibition with extensive selectivity profiling across multiple pathways; widely replicated by subsequent studies","pmids":["12065756"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Selective kinase inhibition assays, Smad2/3 phosphorylation readouts, cell death assays","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct kinase inhibition with comprehensive receptor selectivity profiling; replicated across multiple endpoints","pmids":["14978253"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Receptor signaling assays, insulin secretion assays in MIN6 cells, receptor isoform-specific ligand-response experiments","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand-receptor specificity established with functional cellular readout, multiple ligands and receptor combinations tested","pmids":["15196700"],"is_preprint":false},{"year":2004,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays with gain- and loss-of-function constructs and downstream pathway characterization","pmids":["15150278"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Generation and analysis of ALK7-knockout mice, compound mutant analysis (ALK7−/−; Nodal+/− and ALK7−/−; ALK4+/−)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic knockout mouse model with compound mutant analysis; clear negative result for early developmental role","pmids":["15485907"],"is_preprint":false},{"year":2006,"finding":"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.","method":"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","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple constructs and orthogonal readouts; single lab","pmids":["17040568"],"is_preprint":false},{"year":2008,"finding":"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.","method":"ALK7-knockout mouse model, activin B knockout, double mutant analysis, in vivo metabolic phenotyping, Ca2+ imaging in islet cells, insulin secretion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with double mutant epistasis, multiple orthogonal readouts (Ca2+ signaling, insulin secretion, metabolic phenotype) establishing pathway placement","pmids":["18480258"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Knockout mouse models (Gdf3−/−, ALK7−/−), high-fat diet challenge, adipose tissue analysis, receptor signaling experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockout mouse models converging on the same pathway with in vivo metabolic phenotyping","pmids":["18480259"],"is_preprint":false},{"year":2012,"finding":"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.","method":"siRNA knockdown, Nodal overexpression, constitutively active Akt/XIAP overexpression, Smad2/3 ablation, caspase-3 Western blot, phospho-Akt assays in INS-1 cells","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss- and gain-of-function approaches in a single cell model; single lab","pmids":["22550067"],"is_preprint":false},{"year":2012,"finding":"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.","method":"ALK7-knockout mouse model, immunofluorescence, in situ hybridization, hormonal assays, histological analysis of ovary/pituitary/hypothalamus, tracttracing","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with tissue-specific localization and multiple reproductive axis phenotypes establishing pathway placement","pmids":["22954591"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — global and tissue-specific knockouts plus acute chemical-genetic inhibition, replicated in mouse and human adipocytes with multiple orthogonal endpoints","pmids":["25161195"],"is_preprint":false},{"year":2015,"finding":"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.","method":"ALK7-knockout mice, cardiac-specific ALK7-transgenic mice, aortic banding, echocardiography, MEK-ERK1/2 pathway analysis, in vitro cardiomyocyte assays","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal knockout/transgenic mouse models with defined molecular pathway (MEK-ERK1/2); single lab","pmids":["26249805"],"is_preprint":false},{"year":2015,"finding":"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.","method":"ALK7-knockout mice, telemetry ECG, Langendorff heart perfusion, whole-cell patch clamp, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with electrophysiological and molecular readouts; single lab, single study","pmids":["26882027"],"is_preprint":false},{"year":2018,"finding":"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.","method":"shRNA knockdown, pharmacological inhibition (SB505124), SMAD2/3 knockdown, invasion/proliferation assays, Western blot, orthotopic zebrafish tumor model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological loss-of-function approaches with in vitro and in vivo validation, Smad isoform specificity defined","pmids":["30401983"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Mouse tumor models (RIP-Tag pancreatic neuroendocrine, luminal breast cancer), experimental metastasis assays, genetic manipulation of ALK7/activin B expression","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo mouse tumor models with genetic manipulation establishing mechanism across independent cancer types","pmids":["31063757"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Organotypic PDAC-on-a-chip 3D culture model, in vivo PDAC mouse models, pathway manipulation assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro organ-on-chip plus in vivo model; pathway identified but molecular details of ALK7 mechanism in ablation are not fully elaborated in the abstract","pmids":["31489365"],"is_preprint":false},{"year":2020,"finding":"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).","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with multiple molecular readouts, pharmacological rescue, and validation in human cells","pmids":["32366358"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Activin E and ACVR1C knockout mouse models, SMAD2/3 signaling assays, lipolysis assays, gene expression analysis (PPARG targets)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockout mouse models establishing ligand-receptor-effector pathway with multiple molecular and metabolic readouts","pmids":["37523551"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with pharmacological combination and defined molecular mechanism; single lab","pmids":["34245608"],"is_preprint":false},{"year":2021,"finding":"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.","method":"shRNA knockdown, overexpression, UV irradiation of NHEK cells, Western blot for SMAD2 phosphorylation and lipogenic genes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined signaling mechanism (SMAD2 phosphorylation); single lab, single cell type","pmids":["33499275"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Knock-in mouse models carrying human ACVR1C missense variants, high-fat diet challenge, metabolic phenotyping, lipolysis assays, ALK7 signaling assays","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent knock-in mouse models with graded signaling defects and comprehensive metabolic phenotyping","pmids":["38307384"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RNA-seq on dorsal hippocampus, overexpression in mice, 5xFAD mouse model, synaptic plasticity measurements, memory behavioral assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function in multiple mouse models with functional synaptic and memory readouts; single lab","pmids":["38714691"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"NAR molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — experimentally validated transcriptional repression mechanism with chromatin analysis; single lab, single study","pmids":["41255711"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Binding assays (GREM1-ACVR1C interaction), SMAD2/3 signaling assays, SNAI1/GREM1 expression analysis, shRNA/pharmacological inhibition, orthotopic in vivo metastasis model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel ligand-receptor interaction with in vivo validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.11.664267"],"is_preprint":true},{"year":2025,"finding":"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.","method":"Orthotopic PDAC metastasis mouse model, 3D microfluidic vessel-on-chip, pharmacological and genetic ALK7 inhibition, β-catenin and MMP pathway analysis, invadosome formation assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo models with defined non-canonical pathway; single lab","pmids":["40616087"],"is_preprint":false},{"year":2015,"finding":"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).","method":"Surface plasmon resonance binding assays, CD and NMR conformational analysis, synthetic peptide mutagenesis","journal":"Journal of peptide science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding reconstitution with SPR and structural analysis but limited to peptide fragments; single lab","pmids":["25588905"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Pharmacological and genetic ALK7 manipulation in murine brown adipocytes, differentiation assays, SMAD3 signaling readouts, cGMP/PKG pathway analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological/genetic tools in primary brown adipocytes; single lab","pmids":["26266090"],"is_preprint":false},{"year":2020,"finding":"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.","method":"AdshALK7 knockdown in bone marrow-derived macrophages and peritoneal macrophages, PPARγ inhibitor (G3335), Oil Red O staining, RT-PCR, Western blot","journal":"Journal of atherosclerosis and thrombosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined downstream effector (PPARγ) and pharmacological rescue; single lab","pmids":["32641645"],"is_preprint":false}],"current_model":"ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that forms complexes with type II receptors (primarily ActRIIB/ActRIIA) and the co-receptor Cripto to transduce signals from Nodal, activin B, activin AB, GDF3, and activin E, principally through Smad2/3 phosphorylation and nuclear translocation; downstream of this canonical pathway, ALK7 negatively regulates adipocyte lipolysis and β-adrenergic signaling (suppressing β3-AR via C/EBPα), limits insulin secretion from pancreatic β-cells by antagonizing activin A-driven Ca2+ influx, suppresses catabolic gene programs (KLF15, POX, ATGL) in brown adipose tissue to preserve energy during fasting, inhibits trophoblast and tumor cell proliferation/survival via G1 arrest and apoptosis, regulates synaptic plasticity and memory in the hippocampus, and controls pubertal onset by epigenetically repressing Mkrn3; in cancer contexts ALK7 can act as either a tumor suppressor (inducing apoptosis via activin B in neuroendocrine and breast cancer) or a pro-metastatic factor (through non-canonical β-catenin-EMT/MMP axes and a GREM1 autocrine loop in pancreatic and colorectal cancers)."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1999,"claim":"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","pmids":["9920806","11084022"],"confidence":"High","gaps":["Used a constitutively active mutant rather than physiological ligand","Smad2 vs Smad3 selectivity of endogenous receptor not resolved"]},{"year":2001,"claim":"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","pmids":["11485994","12063393"],"confidence":"High","gaps":["Cell-type contexts where ALK7 functions endogenously not defined","Quantitative affinities of the receptor-ligand complex not measured"]},{"year":2002,"claim":"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","pmids":["12065756","14978253"],"confidence":"High","gaps":["Inhibitors do not distinguish ALK7 from ALK4/ALK5","No ALK7-selective inhibitor identified"]},{"year":2004,"claim":"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","pmids":["15196700","15485907","15150278"],"confidence":"High","gaps":["Why ALK7 is dispensable for early Nodal signaling despite biochemical responsiveness not fully explained","Full ligand repertoire still incomplete at this point"]},{"year":2008,"claim":"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","pmids":["18480258","18480259"],"confidence":"High","gaps":["Tissue-autonomous vs systemic contributions not separated","Downstream transcriptional effectors of metabolic suppression not yet identified"]},{"year":2014,"claim":"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","pmids":["25161195"],"confidence":"High","gaps":["Molecular link from Smad signaling to β-AR suppression not defined here","Endogenous ligand driving adipose ALK7 not pinpointed"]},{"year":2021,"claim":"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","pmids":["32366358","37523551","34245608","26266090"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38307384","38714691"],"confidence":"Medium","gaps":["Human variant signaling threshold differs from mouse, complicating translation","Mechanism of bidirectional synaptic regulation not defined"]},{"year":2025,"claim":"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","pmids":["41255711","40616087"],"confidence":"Medium","gaps":["GREM1-ACVR1C interaction reported only in a preprint","Switch between tumor-suppressive and pro-metastatic ALK7 output not mechanistically reconciled"]},{"year":null,"claim":"What determines whether ALK7-Smad2/3 signaling is anti-proliferative/tumor-suppressive versus pro-metastatic and non-canonical (β-catenin/MMP) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,27]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,14,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,12,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,18,28]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[26]}],"complexes":[],"partners":["ACVR2B","ACVR2A","TDGF1","NODAL","INHBB","GDF3","INHBE","GREM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NER5","full_name":"Activin receptor type-1C","aliases":["Activin receptor type IC","ACTR-IC","Activin receptor-like kinase 7","ALK-7"],"length_aa":493,"mass_kda":54.9,"function":"Serine/threonine protein kinase which forms a receptor complex on ligand binding. The receptor complex consists of 2 type II and 2 type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators, SMAD2 and SMAD3. Receptor for activin AB, activin B, activin E and NODAL. Upon NODAL binding, activation results in increased apoptosis and reduced proliferation through suppression of AKT signaling and the activation of Smad2-dependent signaling pathway in pancreatic beta-cells, trophoblasts, epithelial or neuronal cells (PubMed:15531507, PubMed:15150278). Acts as a positive regulator for macrophage activation partially through down-regulation of PPARG expression (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8NER5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACVR1C","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACVR1C","total_profiled":1310},"omim":[{"mim_id":"608981","title":"ACTIVIN A RECEPTOR, TYPE IC; ACVR1C","url":"https://www.omim.org/entry/608981"},{"mim_id":"606522","title":"GROWTH/DIFFERENTIATION FACTOR 3; GDF3","url":"https://www.omim.org/entry/606522"},{"mim_id":"602284","title":"BONE MORPHOGENETIC PROTEIN 8B; BMP8B","url":"https://www.omim.org/entry/602284"},{"mim_id":"147390","title":"INHIBIN, BETA B; INHBB","url":"https://www.omim.org/entry/147390"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose 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markers","url":"https://pubmed.ncbi.nlm.nih.gov/38077937","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.11.664267","title":"A Paracrine-to-Autocrine Shunt of GREM1 Fuels Colorectal Cancer Metastasis via ACVR1C","date":"2025-07-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.11.664267","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.605812","title":"Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues","date":"2024-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.605812","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28718,"output_tokens":8522,"usd":0.106992,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18459,"output_tokens":3704,"usd":0.092448,"stage2_stop_reason":"end_turn"},"total_usd":0.19944,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Receptor reconstitution experiments, dominant-negative and constitutively active receptor constructs, Xenopus embryo functional assays, binding assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution experiments with multiple orthogonal methods (binding assays, dominant-negative, constitutively active mutants, in vivo embryo assays), replicated across multiple ligands and conditions in a single rigorous study\",\n      \"pmids\": [\"11485994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Tetracycline-inducible constitutively active ALK7 in PC12 cell line, Smad phosphorylation assays, reporter assays, thymidine incorporation, Western blot, morphological analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — constitutively active mutant with multiple orthogonal readouts (signaling, transcription, proliferation, morphology) in a single controlled study\",\n      \"pmids\": [\"11084022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assays, PAI-1 reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric Smad domain-swap constructs provide orthogonal mechanistic insight; single lab but multiple constructs tested\",\n      \"pmids\": [\"9920806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"FISH chromosomal mapping, recombinant adenovirus infection, Western blot for phospho-Smad2\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional validation by constitutively active construct plus chromosomal mapping; single lab\",\n      \"pmids\": [\"12063393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Small molecule kinase inhibition assays, selective pathway readouts, signaling reporter assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct kinase inhibition with extensive selectivity profiling across multiple pathways; widely replicated by subsequent studies\",\n      \"pmids\": [\"12065756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Selective kinase inhibition assays, Smad2/3 phosphorylation readouts, cell death assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct kinase inhibition with comprehensive receptor selectivity profiling; replicated across multiple endpoints\",\n      \"pmids\": [\"14978253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Receptor signaling assays, insulin secretion assays in MIN6 cells, receptor isoform-specific ligand-response experiments\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand-receptor specificity established with functional cellular readout, multiple ligands and receptor combinations tested\",\n      \"pmids\": [\"15196700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays with gain- and loss-of-function constructs and downstream pathway characterization\",\n      \"pmids\": [\"15150278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Generation and analysis of ALK7-knockout mice, compound mutant analysis (ALK7−/−; Nodal+/− and ALK7−/−; ALK4+/−)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic knockout mouse model with compound mutant analysis; clear negative result for early developmental role\",\n      \"pmids\": [\"15485907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple constructs and orthogonal readouts; single lab\",\n      \"pmids\": [\"17040568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"ALK7-knockout mouse model, activin B knockout, double mutant analysis, in vivo metabolic phenotyping, Ca2+ imaging in islet cells, insulin secretion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with double mutant epistasis, multiple orthogonal readouts (Ca2+ signaling, insulin secretion, metabolic phenotype) establishing pathway placement\",\n      \"pmids\": [\"18480258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse models (Gdf3−/−, ALK7−/−), high-fat diet challenge, adipose tissue analysis, receptor signaling experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knockout mouse models converging on the same pathway with in vivo metabolic phenotyping\",\n      \"pmids\": [\"18480259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Nodal overexpression, constitutively active Akt/XIAP overexpression, Smad2/3 ablation, caspase-3 Western blot, phospho-Akt assays in INS-1 cells\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss- and gain-of-function approaches in a single cell model; single lab\",\n      \"pmids\": [\"22550067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"ALK7-knockout mouse model, immunofluorescence, in situ hybridization, hormonal assays, histological analysis of ovary/pituitary/hypothalamus, tracttracing\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with tissue-specific localization and multiple reproductive axis phenotypes establishing pathway placement\",\n      \"pmids\": [\"22954591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global and tissue-specific knockouts plus acute chemical-genetic inhibition, replicated in mouse and human adipocytes with multiple orthogonal endpoints\",\n      \"pmids\": [\"25161195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"ALK7-knockout mice, cardiac-specific ALK7-transgenic mice, aortic banding, echocardiography, MEK-ERK1/2 pathway analysis, in vitro cardiomyocyte assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockout/transgenic mouse models with defined molecular pathway (MEK-ERK1/2); single lab\",\n      \"pmids\": [\"26249805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"ALK7-knockout mice, telemetry ECG, Langendorff heart perfusion, whole-cell patch clamp, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with electrophysiological and molecular readouts; single lab, single study\",\n      \"pmids\": [\"26882027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition (SB505124), SMAD2/3 knockdown, invasion/proliferation assays, Western blot, orthotopic zebrafish tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological loss-of-function approaches with in vitro and in vivo validation, Smad isoform specificity defined\",\n      \"pmids\": [\"30401983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse tumor models (RIP-Tag pancreatic neuroendocrine, luminal breast cancer), experimental metastasis assays, genetic manipulation of ALK7/activin B expression\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo mouse tumor models with genetic manipulation establishing mechanism across independent cancer types\",\n      \"pmids\": [\"31063757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Organotypic PDAC-on-a-chip 3D culture model, in vivo PDAC mouse models, pathway manipulation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro organ-on-chip plus in vivo model; pathway identified but molecular details of ALK7 mechanism in ablation are not fully elaborated in the abstract\",\n      \"pmids\": [\"31489365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with multiple molecular readouts, pharmacological rescue, and validation in human cells\",\n      \"pmids\": [\"32366358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Activin E and ACVR1C knockout mouse models, SMAD2/3 signaling assays, lipolysis assays, gene expression analysis (PPARG targets)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knockout mouse models establishing ligand-receptor-effector pathway with multiple molecular and metabolic readouts\",\n      \"pmids\": [\"37523551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with pharmacological combination and defined molecular mechanism; single lab\",\n      \"pmids\": [\"34245608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, overexpression, UV irradiation of NHEK cells, Western blot for SMAD2 phosphorylation and lipogenic genes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined signaling mechanism (SMAD2 phosphorylation); single lab, single cell type\",\n      \"pmids\": [\"33499275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in mouse models carrying human ACVR1C missense variants, high-fat diet challenge, metabolic phenotyping, lipolysis assays, ALK7 signaling assays\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent knock-in mouse models with graded signaling defects and comprehensive metabolic phenotyping\",\n      \"pmids\": [\"38307384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq on dorsal hippocampus, overexpression in mice, 5xFAD mouse model, synaptic plasticity measurements, memory behavioral assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function in multiple mouse models with functional synaptic and memory readouts; single lab\",\n      \"pmids\": [\"38714691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"NAR molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — experimentally validated transcriptional repression mechanism with chromatin analysis; single lab, single study\",\n      \"pmids\": [\"41255711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Binding assays (GREM1-ACVR1C interaction), SMAD2/3 signaling assays, SNAI1/GREM1 expression analysis, shRNA/pharmacological inhibition, orthotopic in vivo metastasis model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel ligand-receptor interaction with in vivo validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.11.664267\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Orthotopic PDAC metastasis mouse model, 3D microfluidic vessel-on-chip, pharmacological and genetic ALK7 inhibition, β-catenin and MMP pathway analysis, invadosome formation assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo models with defined non-canonical pathway; single lab\",\n      \"pmids\": [\"40616087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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).\",\n      \"method\": \"Surface plasmon resonance binding assays, CD and NMR conformational analysis, synthetic peptide mutagenesis\",\n      \"journal\": \"Journal of peptide science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding reconstitution with SPR and structural analysis but limited to peptide fragments; single lab\",\n      \"pmids\": [\"25588905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological and genetic ALK7 manipulation in murine brown adipocytes, differentiation assays, SMAD3 signaling readouts, cGMP/PKG pathway analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological/genetic tools in primary brown adipocytes; single lab\",\n      \"pmids\": [\"26266090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"AdshALK7 knockdown in bone marrow-derived macrophages and peritoneal macrophages, PPARγ inhibitor (G3335), Oil Red O staining, RT-PCR, Western blot\",\n      \"journal\": \"Journal of atherosclerosis and thrombosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined downstream effector (PPARγ) and pharmacological rescue; single lab\",\n      \"pmids\": [\"32641645\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that forms complexes with type II receptors (primarily ActRIIB/ActRIIA) and the co-receptor Cripto to transduce signals from Nodal, activin B, activin AB, GDF3, and activin E, principally through Smad2/3 phosphorylation and nuclear translocation; downstream of this canonical pathway, ALK7 negatively regulates adipocyte lipolysis and β-adrenergic signaling (suppressing β3-AR via C/EBPα), limits insulin secretion from pancreatic β-cells by antagonizing activin A-driven Ca2+ influx, suppresses catabolic gene programs (KLF15, POX, ATGL) in brown adipose tissue to preserve energy during fasting, inhibits trophoblast and tumor cell proliferation/survival via G1 arrest and apoptosis, regulates synaptic plasticity and memory in the hippocampus, and controls pubertal onset by epigenetically repressing Mkrn3; in cancer contexts ALK7 can act as either a tumor suppressor (inducing apoptosis via activin B in neuroendocrine and breast cancer) or a pro-metastatic factor (through non-canonical β-catenin-EMT/MMP axes and a GREM1 autocrine loop in pancreatic and colorectal cancers).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #2]. 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 [#6, #11, #21, #29]. 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 [#1, #7, #12, #18]. 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 [#10, #14, #20, #21, #22, #24]. 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 [#13, #25, #26]. In cancer it can also act non-canonically and pro-metastatically through β-catenin–EMT/MMP axes and a GREM1 autocrine SMAD2/3 loop [#27, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that ALK7 is a functional Smad-activating kinase receptor, defining its core signaling output before its ligands were known.\",\n      \"evidence\": \"Constitutively active ALK7 (T194D) transfection with chimeric Smad domain-swap constructs and PAI-1 reporter assays\",\n      \"pmids\": [\"9920806\", \"11084022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used a constitutively active mutant rather than physiological ligand\", \"Smad2 vs Smad3 selectivity of endogenous receptor not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Receptor reconstitution, dominant-negative/constitutively active constructs, and Xenopus embryo functional assays\",\n      \"pmids\": [\"11485994\", \"12063393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type contexts where ALK7 functions endogenously not defined\", \"Quantitative affinities of the receptor-ligand complex not measured\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided pharmacological tools (SB-431542, SB-505124) that selectively block ALK4/ALK5/ALK7 kinase activity, enabling specific interrogation of ALK7-dependent Smad2/3 signaling.\",\n      \"evidence\": \"Small-molecule kinase inhibition with selectivity profiling across ALK family and MAPK pathways\",\n      \"pmids\": [\"12065756\", \"14978253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitors do not distinguish ALK7 from ALK4/ALK5\", \"No ALK7-selective inhibitor identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Receptor isoform-specific ligand-response assays in MIN6 cells and ALK7-knockout/compound-mutant mouse analysis\",\n      \"pmids\": [\"15196700\", \"15485907\", \"15150278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ALK7 is dispensable for early Nodal signaling despite biochemical responsiveness not fully explained\", \"Full ligand repertoire still incomplete at this point\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established ALK7 as a negative regulator of metabolism, linking activin B/GDF3-ALK7 signaling to insulin secretion control and adipose accumulation in vivo.\",\n      \"evidence\": \"ALK7-, activin B-, and Gdf3-knockout mice with double-mutant epistasis, Ca2+ imaging, and high-fat-diet metabolic phenotyping\",\n      \"pmids\": [\"18480258\", \"18480259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-autonomous vs systemic contributions not separated\", \"Downstream transcriptional effectors of metabolic suppression not yet identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the adipocyte mechanism: ALK7 cell-autonomously suppresses β-adrenergic signaling and lipolysis, identifying it as a brake on catecholamine-driven fat mobilization.\",\n      \"evidence\": \"Global, fat-specific, and acute chemical-genetic ALK7 inhibition in mice plus mouse and human adipocyte lipolysis assays\",\n      \"pmids\": [\"25161195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from Smad signaling to β-AR suppression not defined here\", \"Endogenous ligand driving adipose ALK7 not pinpointed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Tissue-specific and conditional ALK7 knockouts, activin E knockout, fasting/cold challenge, and downstream gene expression analysis\",\n      \"pmids\": [\"32366358\", \"37523551\", \"34245608\", \"26266090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knock-in mouse models of human variants with metabolic phenotyping; hippocampal RNA-seq, overexpression, and 5xFAD memory/plasticity assays\",\n      \"pmids\": [\"38307384\", \"38714691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human variant signaling threshold differs from mouse, complicating translation\", \"Mechanism of bidirectional synaptic regulation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ALK7 mechanism to epigenetic gene control and non-canonical oncogenic signaling, including Kap1-mediated Mkrn3 repression and β-catenin/GREM1-driven metastasis.\",\n      \"evidence\": \"Acvr1c activation with Kap1 recruitment and histone-modification analysis; GREM1 binding assays and orthotopic CRC/PDAC metastasis models with ALK7 inhibition\",\n      \"pmids\": [\"41255711\", \"40616087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GREM1-ACVR1C interaction reported only in a preprint\", \"Switch between tumor-suppressive and pro-metastatic ALK7 output not mechanistically reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines whether ALK7-Smad2/3 signaling is anti-proliferative/tumor-suppressive versus pro-metastatic and non-canonical (β-catenin/MMP) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 27]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 14, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 12, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 18, 28]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACVR2B\", \"ACVR2A\", \"TDGF1\", \"NODAL\", \"INHBB\", \"GDF3\", \"INHBE\", \"GREM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}