{"gene":"ACVR1C","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2001,"finding":"ALK7 (ACVR1C) acts as a type I receptor for Nodal proteins, collaborating with ActRIIB to confer responsiveness to Xnr1 and Nodal; both receptors independently bind Xnr1. Cripto can independently interact with both Xnr1 and ALK7 and greatly enhances ALK7/ActRIIB responsiveness to Nodal. A constitutively active ALK7 mimics mesendoderm-inducing activity of Xnr1, while dominant-negative ALK7 specifically blocks Nodal and Xnr1 activities.","method":"Receptor reconstitution experiments, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution, dominant-negative/active constructs with specific phenotypic readouts, replicated across multiple ligands","pmids":["11485994"],"is_preprint":false},{"year":2002,"finding":"SB-431542 selectively inhibits the kinase activity of ALK4, ALK5, and ALK7 (but not other ALK family members), blocking endogenous activin, TGF-beta, and Nodal signaling without affecting BMP signaling or ERK/JNK/p38 MAP kinase pathways.","method":"In vitro kinase assay, cell-based signaling assays with selective ALK inhibitor","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzyme inhibition with extensive selectivity profiling, widely replicated","pmids":["12065756"],"is_preprint":false},{"year":1999,"finding":"Constitutively active ALK7 (T194D) activates Smad2 and Smad3, translocating them to the nucleus and inducing PAI-1 promoter activity. The MH1 domain of Smad2 has an inhibitory effect on nuclear localization, while the MH1 domain of Smad3 is required for full activation downstream of ALK7.","method":"Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assay, PAI-1 promoter-reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple reporter and localization experiments with domain-swap constructs in a single study","pmids":["9920806"],"is_preprint":false},{"year":2000,"finding":"Constitutively active ALK7 activates Smad2 and Smad3 (but not Smad1), ERK, and JNK signaling; induces Smad7, c-fos, and PAI-1 expression; inhibits proliferation via upregulation of p15INK4B and p21; and drives morphological differentiation with actin rearrangement in PC12 cells.","method":"Tetracycline-inducible constitutively active ALK7 expression in PC12 cells, thymidine incorporation, reporter assays, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — inducible system with multiple orthogonal readouts including signaling, proliferation, and morphology","pmids":["11084022"],"is_preprint":false},{"year":2001,"finding":"Human ALK7 (ACVR1C) gene maps to chromosome 2q24.1→q3; constitutively active ALK7 (Ad-caALK7) infection of MIN6 insulinoma cells induces marked phosphorylation of Smad2, confirming functional ALK7 signaling in pancreatic beta cells.","method":"FISH mapping, recombinant adenovirus infection, Western blot for pSmad2","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal localization by FISH and functional signaling validation in relevant cell type","pmids":["12063393"],"is_preprint":false},{"year":2002,"finding":"Alternative splicing of the human ALK7 gene produces four protein variants: full-length ALK7, truncated ALK7 (tALK7, lacking first 50 amino acids of ligand-binding domain), and two soluble forms (sALK7a, sALK7b) lacking transmembrane and GS domains. All isoforms are expressed in human placenta in a developmentally regulated manner.","method":"PCR cloning, Western blot, RT-PCR, exon mapping","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning and expression characterization with multiple methods","pmids":["12606401"],"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. Nodal/ALK7 induces G1 arrest by increasing p27 and decreasing Cdk2 and cyclin D1.","method":"Overexpression of Nodal and constitutively active/kinase-deficient ALK7, dominant-negative Smad2/3, BrdU proliferation assay, flow cytometry, caspase-3 Western blot, Hoechst staining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with gain- and loss-of-function constructs, epistasis through dominant-negative Smad","pmids":["15150278"],"is_preprint":false},{"year":2004,"finding":"Activin AB and activin B are ligands for ALK7; the combination of ActRIIA and ALK7 (preferred by activin AB and activin B, but not activin A) mediates activin-induced insulin secretion from MIN6 beta cells. Activin A signals preferentially through ActRIIA/ALK4.","method":"Receptor reconstitution in cell lines, insulin secretion assay","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 — receptor reconstitution with functional readout, distinguishing ligand-receptor pairing specificity","pmids":["15196700"],"is_preprint":false},{"year":2004,"finding":"ALK7 knockout mice develop normally with no left-right patterning defects, demonstrating that ALK7 is dispensable for Nodal-mediated mesendoderm formation and left-right patterning in the mouse but may have tissue-specific roles in metabolic and neurological function.","method":"ALK7 knockout mouse generation and characterization, histological analysis, compound mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — comprehensive knockout mouse analysis with multiple endpoints and compound mutants","pmids":["15485907"],"is_preprint":false},{"year":2004,"finding":"SB-505124 selectively inhibits ALK4-, ALK5-, and ALK7-dependent Smad2/3 activation without affecting ALK1, ALK2, ALK3, or ALK6 signaling, and blocks TGF-beta-induced MAPK activation and cell death.","method":"Cell-based Smad2/3 phosphorylation assay, selective ALK inhibitor characterization","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro and cell-based enzyme inhibition with comprehensive selectivity profiling","pmids":["14978253"],"is_preprint":false},{"year":2006,"finding":"ALK7 can mediate activin B signaling in gonadotrope cells to stimulate FSHbeta transcription through Smad3; constitutively active ALK7 and ALK4 both stimulate Smad2/3 phosphorylation and Fshb promoter activity, effects that are blocked by Smad3 depletion.","method":"Constitutively active and kinase-deficient ALK receptor transfection, Fshb promoter-reporter assay, shRNA Smad3 knockdown, RT-PCR, Western blot","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple constructs and epistasis via shRNA in relevant cell type","pmids":["17040568"],"is_preprint":false},{"year":2008,"finding":"ALK7 negatively regulates glucose-stimulated insulin secretion in pancreatic beta cells through mediating activin B effects on Ca2+ signaling; ALK7 and activin B function in a common pathway, as double knockouts show no additive hyperinsulinemia. Activin A and activin B have opposing effects on Ca2+ influx.","method":"ALK7 and activin B knockout mice, calcium imaging, insulin secretion assay, double mutant epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse, calcium imaging, genetic epistasis with double mutant","pmids":["18480258"],"is_preprint":false},{"year":2008,"finding":"GDF3 signals through ALK7 (and co-receptor Cripto) in adipose tissue to regulate adipose accumulation; Gdf3-/- and Alk7-/- mice both show reduced fat mass and partial resistance to high-fat diet-induced obesity.","method":"Knockout mouse phenotyping, high-fat diet challenge, ligand-receptor signaling assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — parallel knockout models with concordant metabolic phenotypes, demonstrating ligand-receptor relationship in vivo","pmids":["18480258","18480259"],"is_preprint":false},{"year":2012,"finding":"Nodal activates ALK7 signaling to induce apoptosis in pancreatic beta cells through Smad2/3-caspase-3 activation and suppression of Akt/XIAP; siRNA-mediated ALK7 knockdown significantly attenuates Nodal-induced apoptosis.","method":"siRNA knockdown of ALK7, Nodal overexpression, caspase-3 assay, Akt phosphorylation Western blot, XIAP expression analysis, constitutively active Akt rescue","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary functional assays with specific knockdown and rescue experiments","pmids":["22550067"],"is_preprint":false},{"year":2012,"finding":"ALK7 is expressed in SF1-positive granulosa cells, FSH gonadotrophs, and NPY-expressing arcuate neurons; Alk7 knockout females show delayed puberty, abnormal estrous cyclicity, premature follicle depletion, impaired gonadotropin responses, and reduced NPY/AgRP innervation to medial preoptic area.","method":"Alk7 knockout mouse characterization, immunohistochemistry, hormone measurements, NPY/AgRP circuit analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — comprehensive knockout phenotyping with cell-type-specific localization and neuroendocrine circuit analysis","pmids":["22954591"],"is_preprint":false},{"year":2014,"finding":"ALK7 mediates diet-induced catecholamine resistance in adipose tissue; fat-specific Alk7 knockout enhances adipose beta-adrenergic receptor expression, beta-adrenergic signaling, mitochondrial biogenesis, lipolysis, and energy expenditure, reducing obesity. Acute chemical-genetic ALK7 inhibition recapitulates these effects. ALK7 activation reduces beta-AR-mediated signaling and lipolysis cell-autonomously in mouse and human adipocytes.","method":"Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, beta-adrenergic signaling assays, lipolysis assays, energy expenditure measurement, human adipocyte experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple genetic models, chemical-genetic validation, human cell confirmation, multiple orthogonal metabolic readouts","pmids":["25161195"],"is_preprint":false},{"year":2015,"finding":"ALK7 protects against pathological cardiac hypertrophy; ALK7 disruption aggravates cardiac hypertrophy and fibrosis while cardiac-specific ALK7 overexpression is protective. Mechanistically, ALK7-dependent cardioprotection operates through inhibition of the MEK-ERK1/2 signaling pathway.","method":"ALK7 knockout and cardiac-specific transgenic mice, aortic banding model, echocardiography, in vitro cardiomyocyte assays, MEK-ERK1/2 pathway analysis","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 — complementary KO and overexpression in vivo models with pathway mechanism identified","pmids":["26249805"],"is_preprint":false},{"year":2015,"finding":"Nodal fragments encompassing the pre-helix loop and H3 helix (residues 44-67) bind directly to recombinant ALK7 and ALK4 in vitro by surface plasmon resonance; residue Y58 of Nodal is implicated in recognition by both ALK7 and the co-receptor Cripto.","method":"Surface plasmon resonance binding assays, NMR/CD structural characterization, site-directed mutagenesis of Nodal peptides","journal":"Journal of peptide science","confidence":"Medium","confidence_rationale":"Tier 1 — direct binding assay with mutagenesis identifying specific contact residues","pmids":["25588905"],"is_preprint":false},{"year":2015,"finding":"ALK7 is upregulated by cGMP/PKG signaling during brown adipocyte differentiation; activin AB activates ALK7-SMAD3 signaling in brown preadipocytes to suppress PPARgamma and differentiation, while ALK7 activation during late differentiation reduces lipid content but enhances UCP1 expression.","method":"Pharmacological and genetic tools in murine brown adipocytes, differentiation assays, SMAD3 signaling analysis, cGMP pathway modulation","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic/pharmacological interventions in relevant cell type with mechanistic pathway identification","pmids":["26266090"],"is_preprint":false},{"year":2016,"finding":"ALK7 maintains cardiac repolarization by supporting expression of repolarizing K+ channels; Alk7-/- cardiomyocytes show reduced Ito and IK1 currents, decreased Kv4.2 and KCHIP2 expression, prolonged action potential duration, and increased ventricular arrhythmia susceptibility.","method":"Alk7 knockout mice, telemetry ECG, Langendorff perfusion, whole-cell patch clamp, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — knockout with electrophysiological and molecular mechanistic characterization","pmids":["26882027"],"is_preprint":false},{"year":2018,"finding":"ACVR1C/ALK7 signaling through SMAD2 (not SMAD3) promotes invasion, growth, and survival of retinoblastoma cells; pharmacological inhibition with SB505124 or shRNA knockdown suppresses invasion and reduces ZEB1/Snail mesenchymal markers. ALK7 knockdown reduces tumor spread in an orthotopic zebrafish model.","method":"shRNA knockdown, pharmacological inhibition, invasion assays, apoptosis assays, zebrafish orthotopic model, Western blot","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary loss-of-function approaches (shRNA + pharmacological) with in vitro and in vivo validation","pmids":["30401983"],"is_preprint":false},{"year":2019,"finding":"ALK7 activated by activin B induces apoptosis in neoplastic cells, acting as a tumor suppressor barrier; during tumorigenesis, cancer cells evade this by downregulating activin B and/or ALK7. Suppression of ALK7 enhances metastatic seeding in mouse models of pancreatic neuroendocrine and luminal breast cancer.","method":"Functional studies in mouse cancer models, experimental metastasis assays, ALK7 expression modulation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic models with mechanistic pathway (activin B-ALK7-apoptosis axis) validated in multiple cancer types","pmids":["31063757"],"is_preprint":false},{"year":2019,"finding":"The activin-ALK7 pathway mediates endothelial ablation by pancreatic ductal adenocarcinoma; PDAC cells use ALK7 signaling to destroy endothelial cells in a 3D organotypic tumor-on-a-chip model and in vivo PDAC models, contributing to tumor hypovascularity.","method":"3D organotypic PDAC-on-a-chip model, in vivo PDAC models, pharmacological inhibition of ALK7","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — novel organotypic model with in vivo confirmation, pathway-specific inhibition","pmids":["31489365"],"is_preprint":false},{"year":2020,"finding":"ALK7 in brown adipose tissue limits catabolic responses to nutrient stress; BAT-specific ALK7 deletion causes fasting-induced hypothermia due to exaggerated catabolism, with increased KLF15, proline dehydrogenase (POX), and ATGL expression. ALK7 ligand stimulation suppresses POX and KLF15 in brown adipocytes. Glucocorticoid receptor antagonist (RU486) normalizes KLF15/POX in mutant BAT, implicating excessive glucocorticoid signaling.","method":"BAT-specific Alk7 conditional knockout, fasting/cold challenge, gene expression analysis, ligand stimulation of human brown adipocytes, RU486 pharmacological rescue","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific knockout with multiple functional readouts and pharmacological rescue identifying downstream pathway","pmids":["32366358"],"is_preprint":false},{"year":2021,"finding":"Activin E (INHBE) signals through ACVR1C to suppress beta-agonist-induced lipolysis in adipose tissue, activating SMAD2/3 signaling and suppressing PPARgamma target genes; loss of activin E or ACVR1C increases fat utilization and drives PPARgamma-regulated gene signatures indicative of healthy adipose function.","method":"Activin E and ACVR1C knockout mice, SMAD2/3 signaling assay, lipolysis assay, RNA-seq, ligand-receptor identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — parallel ligand and receptor knockouts with mechanistic pathway (SMAD2/3, PPARgamma) validated by multiple methods","pmids":["37523551"],"is_preprint":false},{"year":2021,"finding":"Conditional ALK7 ablation in adipocytes synergizes with low-fat diet switch or anti-inflammatory treatment (Na-salicylate) to enhance lipolysis and energy expenditure; mechanistically, this combination strongly upregulates beta3-AR expression and its upstream regulator C/EBPalpha.","method":"Conditional adipocyte-specific Alk7 knockout in obese mice, pharmacological treatment, beta3-AR/C/EBPalpha expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — conditional knockout with mechanistic pathway (beta3-AR/C/EBPalpha) in relevant physiological context","pmids":["34245608"],"is_preprint":false},{"year":2021,"finding":"ACVR1C signaling through SMAD2 phosphorylation regulates SREBP1 and ACC expression in keratinocytes; UV irradiation decreases ACVR1C and epidermal triglyceride synthesis, effects modulated by ACVR1C knockdown or overexpression.","method":"shRNA knockdown and overexpression, UV irradiation, Western blot for pSMAD2, lipogenic gene expression analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional gain/loss-of-function with SMAD2 pathway connection, single lab","pmids":["33499275"],"is_preprint":false},{"year":2024,"finding":"Human ACVR1C missense variants (I195T, I482V, N150H) have graded effects on ALK7 signaling and metabolic phenotype in knock-in mice: I195T phenocopies null mutants (impaired ALK7 signaling, HFD-obesity resistance, enhanced lipolysis); I482V shows partial phenotype; N150H is metabolically indistinguishable from wild type at normal ligand concentrations but shows reduced signaling at low ligand levels.","method":"Knock-in mouse models for each human variant, high-fat diet challenge, ALK7 signaling assays, lipolysis assays, fat mass measurement","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1-2 — three independent knock-in alleles with mechanistic ALK7 signaling characterization, connecting human variants to function","pmids":["38307384"],"is_preprint":false},{"year":2024,"finding":"ACVR1C expression is epigenetically regulated at its promoter by exercise (alleviating repression); ACVR1C activation suppresses Mkrn3 via Smad2/3 signaling, involving KAP1 recruitment and repressive histone modifications. ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice; overexpression of Acvr1c enables learning in aged/5xFAD mice.","method":"RNA-seq of dorsal hippocampus, epigenetic analysis (ChIP), Acvr1c overexpression in mice, synaptic plasticity assays, memory behavior tests","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (ChIP, behavior, electrophysiology) but novel context (memory/hippocampus) from single lab","pmids":["38714691"],"is_preprint":false},{"year":2025,"finding":"Acvr1c activation suppresses Mkrn3 expression via Smad2/3 signaling with KAP1 recruitment and repressive histone modifications at the Mkrn3 locus, providing a mechanism for pubertal timing regulation.","method":"RNA-seq correlation analysis, experimental validation of Acvr1c activation, ChIP for KAP1 and histone marks, Smad2/3 signaling assays","journal":"NAR molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic ChIP and signaling validation, single study","pmids":["41255711"],"is_preprint":false},{"year":2025,"finding":"In pancreatic cancer, ALK7 drives metastasis through two non-canonical pathways: ALK7-beta-catenin-EMT (enhancing tumor cell motility) and ALK7-beta-catenin-MMP (upregulating MMPs, ECM degradation, invadosome formation, vascular basement membrane breakdown, and intravasation). Both pharmacological and genetic ALK7 inhibition suppress metastasis in orthotopic models and 3D microfluidic vessel-on-chip platforms.","method":"Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic knockdown/knockout, pharmacological inhibition, MMP inhibition, beta-catenin pathway analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems and pathway validation, single lab but comprehensive","pmids":["40616087"],"is_preprint":false},{"year":2025,"finding":"GREM1 binds ACVR1C as a novel high-affinity epithelial receptor, activating SMAD2/3 signaling which upregulates SNAI1 and GREM1 itself, establishing a positive feedback autocrine loop that sustains EMT and promotes colorectal cancer metastasis.","method":"Binding assays identifying ACVR1C as GREM1 receptor, SMAD2/3 signaling assays, in vivo metastasis models, feedback loop characterization","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — novel receptor-ligand identification with downstream pathway and in vivo validation, but preprint","pmids":[],"is_preprint":true}],"current_model":"ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that forms complexes with type II receptors (ActRIIA/B) and co-receptors (Cripto) to transduce signals from Nodal, activin B, activin AB, GDF3, and activin E (INHBE), primarily through phosphorylation and nuclear translocation of Smad2/3, which regulate transcriptional programs controlling adipose lipolysis, energy homeostasis, pancreatic beta-cell insulin secretion, neuronal differentiation, trophoblast invasion, cardiac function, and tumor suppression/metastasis depending on cell context."},"narrative":{"teleology":[{"year":1999,"claim":"The first mechanistic evidence that ALK7 signals through the Smad pathway was established when constitutively active ALK7 was shown to activate Smad2 and Smad3 (but not Smad1) and drive their nuclear translocation, defining ALK7 as an activin/TGF-β-branch type I receptor.","evidence":"Constitutively active ALK7 transfection with chimeric Smad constructs, nuclear translocation assays, and PAI-1 promoter-reporter in cell lines","pmids":["9920806"],"confidence":"Medium","gaps":["Single study without identification of the endogenous ligand","Domain requirements for Smad2 vs Smad3 activation not independently validated"]},{"year":2000,"claim":"ALK7 was shown to have pleiotropic cellular effects beyond Smad activation—inducing growth arrest (via p15INK4B/p21), ERK/JNK activation, and neuronal differentiation—establishing it as a multifunctional signaling receptor.","evidence":"Tetracycline-inducible constitutively active ALK7 in PC12 cells with proliferation, reporter, and morphological assays","pmids":["11084022"],"confidence":"High","gaps":["Endogenous ligand for ALK7 in neuronal cells not identified","ERK/JNK activation mechanism (direct vs indirect) unresolved"]},{"year":2001,"claim":"The identity of ALK7's physiological ligand was resolved when Nodal was shown to signal through an ALK7/ActRIIB complex, with the co-receptor Cripto greatly enhancing responsiveness, explaining how Nodal achieves cell-type-specific signaling.","evidence":"Receptor reconstitution, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays","pmids":["11485994"],"confidence":"High","gaps":["Whether ALK7 has Nodal-independent ligands was unknown","Structural basis of Cripto-ALK7 interaction unresolved"]},{"year":2002,"claim":"Development of selective small-molecule inhibitors (SB-431542) that block ALK4/5/7 kinase activity provided pharmacological tools confirming ALK7's kinase-dependent signaling mechanism and enabling pathway dissection.","evidence":"In vitro kinase assay and cell-based signaling assays with extensive selectivity profiling","pmids":["12065756"],"confidence":"High","gaps":["SB-431542 cannot distinguish ALK7 from ALK4/ALK5 effects","No ALK7-selective inhibitor developed"]},{"year":2004,"claim":"The ligand repertoire of ALK7 was expanded beyond Nodal when activin B and activin AB were identified as ALK7 ligands that preferentially pair with ActRIIA (not ActRIIB), and this combination was shown to regulate insulin secretion in β-cells—establishing ALK7's metabolic role.","evidence":"Receptor reconstitution in cell lines with insulin secretion functional readout; parallel Nodal-ALK7 apoptosis studies in trophoblast","pmids":["15196700","15150278"],"confidence":"High","gaps":["In vivo validation of activin B–ALK7 axis in β-cells pending","Downstream mechanism linking ALK7 to insulin exocytosis machinery unknown"]},{"year":2004,"claim":"ALK7 knockout mice developed normally without left-right patterning defects, demonstrating that ALK7 is dispensable for canonical Nodal functions in embryogenesis and redirecting the field toward tissue-specific metabolic and neurological roles.","evidence":"Global ALK7 knockout mouse generation with comprehensive histological and compound mutant analysis","pmids":["15485907"],"confidence":"High","gaps":["Metabolic phenotypes of knockout not yet characterized","Compensatory mechanisms by ALK4 not excluded"]},{"year":2008,"claim":"Genetic epistasis with activin B and ALK7 double knockouts proved they function in a common pathway to negatively regulate glucose-stimulated insulin secretion through Ca²⁺ signaling, while parallel studies showed GDF3 signals through ALK7/Cripto to regulate adipose accumulation.","evidence":"Single and double knockout mice with calcium imaging, insulin secretion, and high-fat diet metabolic phenotyping","pmids":["18480258","18480259"],"confidence":"High","gaps":["Molecular link between ALK7-Smad and Ca²⁺ channel regulation not identified","Relative contributions of activin B vs GDF3 in adipose tissue unclear"]},{"year":2014,"claim":"The central adipose mechanism was established: ALK7 mediates diet-induced catecholamine resistance by suppressing β-adrenergic receptor expression and lipolysis cell-autonomously, and acute chemical-genetic inhibition recapitulated genetic ablation effects, validating ALK7 as a druggable anti-obesity target.","evidence":"Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, β-AR signaling and lipolysis assays in mouse and human adipocytes","pmids":["25161195"],"confidence":"High","gaps":["Mechanism by which Smad2/3 suppresses β-AR transcription not defined","Human genetic validation lacking"]},{"year":2015,"claim":"ALK7 was shown to protect against pathological cardiac hypertrophy through MEK-ERK1/2 inhibition, and separately to regulate brown adipocyte differentiation via Smad3-PPARγ signaling, revealing tissue-specific non-canonical pathway usage.","evidence":"Cardiac-specific transgenic and knockout mice with aortic banding; brown adipocyte differentiation assays with pharmacological/genetic tools","pmids":["26249805","26266090"],"confidence":"Medium","gaps":["Single-lab cardiac studies await independent replication","Whether ALK7 directly inhibits MEK-ERK or acts through an intermediate not resolved","Brown adipocyte findings not confirmed in vivo"]},{"year":2019,"claim":"ALK7 was established as a tumor suppressor: activin B–ALK7 induces apoptosis as a barrier to metastatic seeding, and cancer cells evade this by downregulating ALK7 or activin B—while paradoxically, in PDAC, ALK7 signaling destroys endothelial cells contributing to tumor hypovascularity.","evidence":"In vivo mouse models of pancreatic neuroendocrine cancer, luminal breast cancer, and PDAC with genetic ALK7 modulation and organotypic tumor-on-a-chip","pmids":["31063757","31489365"],"confidence":"High","gaps":["Context-dependent switch from tumor suppressor to pro-metastatic signaling unexplained mechanistically","Patient-derived tumor ALK7 expression patterns not systematically characterized"]},{"year":2021,"claim":"Activin E (INHBE) was identified as a new ALK7 ligand that suppresses lipolysis via Smad2/3 and PPARγ target gene repression, while separately ALK7 was shown to regulate Mkrn3 expression through Smad2/3-KAP1 epigenetic repression, expanding ALK7's roles to include pubertal timing and epigenetic regulation.","evidence":"Parallel activin E and ACVR1C knockout mice with RNA-seq and lipolysis assays; ChIP for KAP1 and histone marks at Mkrn3 locus","pmids":["37523551","34245608"],"confidence":"High","gaps":["Whether INHBE is the primary ALK7 ligand in human adipose unknown","Mkrn3 regulation validated only in mouse hippocampus, relevance to human puberty not tested"]},{"year":2024,"claim":"Human genetic variants in ACVR1C were functionally validated through knock-in mice, showing graded allelic effects on ALK7 signaling and metabolic phenotype—I195T phenocopies null (obesity resistance), I482V is partial, N150H is near-normal—directly connecting human sequence variation to receptor function.","evidence":"Three independent knock-in mouse models with high-fat diet challenge, ALK7 signaling quantification, and lipolysis assays","pmids":["38307384"],"confidence":"High","gaps":["Human population-level metabolic phenotyping of carriers not completed","Structural basis for graded signaling defects not resolved"]},{"year":2024,"claim":"ALK7 was linked to synaptic plasticity and memory: hippocampal Acvr1c overexpression rescued learning deficits in aged and 5xFAD Alzheimer's model mice, with exercise alleviating epigenetic repression at the Acvr1c promoter.","evidence":"RNA-seq of dorsal hippocampus, epigenetic analysis, Acvr1c overexpression, electrophysiology, and behavioral memory tests in mice","pmids":["38714691"],"confidence":"Medium","gaps":["Single-lab finding in novel context requires independent replication","Endogenous ALK7 ligand in hippocampus not identified","Mechanism linking Smad signaling to synaptic plasticity genes undefined"]},{"year":2025,"claim":"In pancreatic cancer, ALK7 was shown to drive metastasis through non-canonical β-catenin–EMT and β-catenin–MMP pathways promoting intravasation, redefining ALK7 as context-dependently pro-metastatic rather than purely tumor-suppressive.","evidence":"Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic and pharmacological ALK7 inhibition, β-catenin/MMP pathway analysis","pmids":["40616087"],"confidence":"Medium","gaps":["Single-lab study; non-canonical β-catenin pathway not validated independently","How ALK7 switches from canonical Smad to non-canonical β-catenin signaling unknown","Therapeutic window for ALK7 inhibition in cancer vs metabolic disease unresolved"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis of ALK7 ligand selectivity and co-receptor requirement, (2) the molecular switch between canonical Smad and non-canonical (β-catenin, ERK) pathway engagement, (3) whether ALK7 can be selectively targeted therapeutically given shared inhibitor sensitivity with ALK4/ALK5, and (4) the identity and role of ALK7 ligands in the CNS.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of ALK7 with any ligand","No ALK7-selective small molecule inhibitor reported","CNS ligand identity unknown","Patient stratification criteria for ALK7-targeted therapy undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,16,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,15,23,24,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,13,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,21,30]}],"complexes":["ALK7/ActRIIB","ALK7/ActRIIA"],"partners":["ACVR2A","ACVR2B","TDGF1","SMAD2","SMAD3","NODAL","INHBB","INHBE"],"other_free_text":[]},"mechanistic_narrative":"ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that transduces signals from multiple ligands—Nodal, activin B, activin AB, GDF3, and activin E (INHBE)—through phosphorylation of Smad2/3 to regulate diverse processes including adipose metabolism, pancreatic β-cell function, neuronal differentiation, cardiac homeostasis, reproductive neuroendocrine circuits, and tumor suppression. In adipose tissue, ALK7 suppresses β-adrenergic receptor expression and lipolysis, and its genetic ablation confers resistance to diet-induced obesity and enhances energy expenditure by upregulating β3-AR/C/EBPα and mitochondrial biogenesis [PMID:25161195, PMID:37523551, PMID:38307384]. In pancreatic β-cells, activin B–ALK7 signaling negatively regulates glucose-stimulated insulin secretion through modulation of Ca²⁺ influx, while Nodal–ALK7 signaling induces apoptosis via Smad2/3-dependent caspase-3 activation and Akt/XIAP suppression [PMID:18480258, PMID:22550067]. ALK7 also functions as a tumor suppressor barrier—activin B–ALK7 induces apoptosis in neoplastic cells, and cancer cells evade this by downregulating ALK7 or its ligands—though in pancreatic ductal adenocarcinoma ALK7 can paradoxically promote metastasis through non-canonical β-catenin–MMP pathways [PMID:31063757, PMID:40616087]."},"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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Cripto can independently interact with both Xnr1 and ALK7 and greatly enhances ALK7/ActRIIB responsiveness to Nodal. A constitutively active ALK7 mimics mesendoderm-inducing activity of Xnr1, while dominant-negative ALK7 specifically blocks Nodal and Xnr1 activities.\",\n      \"method\": \"Receptor reconstitution experiments, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution, dominant-negative/active constructs with specific phenotypic readouts, replicated across multiple ligands\",\n      \"pmids\": [\"11485994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SB-431542 selectively inhibits the kinase activity of ALK4, ALK5, and ALK7 (but not other ALK family members), blocking endogenous activin, TGF-beta, and Nodal signaling without affecting BMP signaling or ERK/JNK/p38 MAP kinase pathways.\",\n      \"method\": \"In vitro kinase assay, cell-based signaling assays with selective ALK inhibitor\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzyme inhibition with extensive selectivity profiling, widely replicated\",\n      \"pmids\": [\"12065756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Constitutively active ALK7 (T194D) activates Smad2 and Smad3, translocating them to the nucleus and inducing PAI-1 promoter activity. The MH1 domain of Smad2 has an inhibitory effect on nuclear localization, while the MH1 domain of Smad3 is required for full activation downstream of ALK7.\",\n      \"method\": \"Constitutively active ALK7 transfection, chimeric Smad constructs, nuclear translocation assay, PAI-1 promoter-reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple reporter and localization experiments with domain-swap constructs in a single study\",\n      \"pmids\": [\"9920806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Constitutively active ALK7 activates Smad2 and Smad3 (but not Smad1), ERK, and JNK signaling; induces Smad7, c-fos, and PAI-1 expression; inhibits proliferation via upregulation of p15INK4B and p21; and drives morphological differentiation with actin rearrangement in PC12 cells.\",\n      \"method\": \"Tetracycline-inducible constitutively active ALK7 expression in PC12 cells, thymidine incorporation, reporter assays, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — inducible system with multiple orthogonal readouts including signaling, proliferation, and morphology\",\n      \"pmids\": [\"11084022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human ALK7 (ACVR1C) gene maps to chromosome 2q24.1→q3; constitutively active ALK7 (Ad-caALK7) infection of MIN6 insulinoma cells induces marked phosphorylation of Smad2, confirming functional ALK7 signaling in pancreatic beta cells.\",\n      \"method\": \"FISH mapping, recombinant adenovirus infection, Western blot for pSmad2\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal localization by FISH and functional signaling validation in relevant cell type\",\n      \"pmids\": [\"12063393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Alternative splicing of the human ALK7 gene produces four protein variants: full-length ALK7, truncated ALK7 (tALK7, lacking first 50 amino acids of ligand-binding domain), and two soluble forms (sALK7a, sALK7b) lacking transmembrane and GS domains. All isoforms are expressed in human placenta in a developmentally regulated manner.\",\n      \"method\": \"PCR cloning, Western blot, RT-PCR, exon mapping\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning and expression characterization with multiple methods\",\n      \"pmids\": [\"12606401\"],\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. Nodal/ALK7 induces G1 arrest by increasing p27 and decreasing Cdk2 and cyclin D1.\",\n      \"method\": \"Overexpression of Nodal and constitutively active/kinase-deficient ALK7, dominant-negative Smad2/3, BrdU proliferation assay, flow cytometry, caspase-3 Western blot, Hoechst staining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with gain- and loss-of-function constructs, epistasis through dominant-negative Smad\",\n      \"pmids\": [\"15150278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Activin AB and activin B are ligands for ALK7; the combination of ActRIIA and ALK7 (preferred by activin AB and activin B, but not activin A) mediates activin-induced insulin secretion from MIN6 beta cells. Activin A signals preferentially through ActRIIA/ALK4.\",\n      \"method\": \"Receptor reconstitution in cell lines, insulin secretion assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor reconstitution with functional readout, distinguishing ligand-receptor pairing specificity\",\n      \"pmids\": [\"15196700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ALK7 knockout mice develop normally with no left-right patterning defects, demonstrating that ALK7 is dispensable for Nodal-mediated mesendoderm formation and left-right patterning in the mouse but may have tissue-specific roles in metabolic and neurological function.\",\n      \"method\": \"ALK7 knockout mouse generation and characterization, histological analysis, compound mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive knockout mouse analysis with multiple endpoints and compound mutants\",\n      \"pmids\": [\"15485907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SB-505124 selectively inhibits ALK4-, ALK5-, and ALK7-dependent Smad2/3 activation without affecting ALK1, ALK2, ALK3, or ALK6 signaling, and blocks TGF-beta-induced MAPK activation and cell death.\",\n      \"method\": \"Cell-based Smad2/3 phosphorylation assay, selective ALK inhibitor characterization\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro and cell-based enzyme inhibition with comprehensive selectivity profiling\",\n      \"pmids\": [\"14978253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ALK7 can mediate activin B signaling in gonadotrope cells to stimulate FSHbeta transcription through Smad3; constitutively active ALK7 and ALK4 both stimulate Smad2/3 phosphorylation and Fshb promoter activity, effects that are blocked by Smad3 depletion.\",\n      \"method\": \"Constitutively active and kinase-deficient ALK receptor transfection, Fshb promoter-reporter assay, shRNA Smad3 knockdown, RT-PCR, Western blot\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple constructs and epistasis via shRNA in relevant cell type\",\n      \"pmids\": [\"17040568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ALK7 negatively regulates glucose-stimulated insulin secretion in pancreatic beta cells through mediating activin B effects on Ca2+ signaling; ALK7 and activin B function in a common pathway, as double knockouts show no additive hyperinsulinemia. Activin A and activin B have opposing effects on Ca2+ influx.\",\n      \"method\": \"ALK7 and activin B knockout mice, calcium imaging, insulin secretion assay, double mutant epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse, calcium imaging, genetic epistasis with double mutant\",\n      \"pmids\": [\"18480258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GDF3 signals through ALK7 (and co-receptor Cripto) in adipose tissue to regulate adipose accumulation; Gdf3-/- and Alk7-/- mice both show reduced fat mass and partial resistance to high-fat diet-induced obesity.\",\n      \"method\": \"Knockout mouse phenotyping, high-fat diet challenge, ligand-receptor signaling assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel knockout models with concordant metabolic phenotypes, demonstrating ligand-receptor relationship in vivo\",\n      \"pmids\": [\"18480258\", \"18480259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nodal activates ALK7 signaling to induce apoptosis in pancreatic beta cells through Smad2/3-caspase-3 activation and suppression of Akt/XIAP; siRNA-mediated ALK7 knockdown significantly attenuates Nodal-induced apoptosis.\",\n      \"method\": \"siRNA knockdown of ALK7, Nodal overexpression, caspase-3 assay, Akt phosphorylation Western blot, XIAP expression analysis, constitutively active Akt rescue\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary functional assays with specific knockdown and rescue experiments\",\n      \"pmids\": [\"22550067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ALK7 is expressed in SF1-positive granulosa cells, FSH gonadotrophs, and NPY-expressing arcuate neurons; Alk7 knockout females show delayed puberty, abnormal estrous cyclicity, premature follicle depletion, impaired gonadotropin responses, and reduced NPY/AgRP innervation to medial preoptic area.\",\n      \"method\": \"Alk7 knockout mouse characterization, immunohistochemistry, hormone measurements, NPY/AgRP circuit analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive knockout phenotyping with cell-type-specific localization and neuroendocrine circuit analysis\",\n      \"pmids\": [\"22954591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ALK7 mediates diet-induced catecholamine resistance in adipose tissue; fat-specific Alk7 knockout enhances adipose beta-adrenergic receptor expression, beta-adrenergic signaling, mitochondrial biogenesis, lipolysis, and energy expenditure, reducing obesity. Acute chemical-genetic ALK7 inhibition recapitulates these effects. ALK7 activation reduces beta-AR-mediated signaling and lipolysis cell-autonomously in mouse and human adipocytes.\",\n      \"method\": \"Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, beta-adrenergic signaling assays, lipolysis assays, energy expenditure measurement, human adipocyte experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple genetic models, chemical-genetic validation, human cell confirmation, multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"25161195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ALK7 protects against pathological cardiac hypertrophy; ALK7 disruption aggravates cardiac hypertrophy and fibrosis while cardiac-specific ALK7 overexpression is protective. Mechanistically, ALK7-dependent cardioprotection operates through inhibition of the MEK-ERK1/2 signaling pathway.\",\n      \"method\": \"ALK7 knockout and cardiac-specific transgenic mice, aortic banding model, echocardiography, in vitro cardiomyocyte assays, MEK-ERK1/2 pathway analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — complementary KO and overexpression in vivo models with pathway mechanism identified\",\n      \"pmids\": [\"26249805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nodal fragments encompassing the pre-helix loop and H3 helix (residues 44-67) bind directly to recombinant ALK7 and ALK4 in vitro by surface plasmon resonance; residue Y58 of Nodal is implicated in recognition by both ALK7 and the co-receptor Cripto.\",\n      \"method\": \"Surface plasmon resonance binding assays, NMR/CD structural characterization, site-directed mutagenesis of Nodal peptides\",\n      \"journal\": \"Journal of peptide science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct binding assay with mutagenesis identifying specific contact residues\",\n      \"pmids\": [\"25588905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ALK7 is upregulated by cGMP/PKG signaling during brown adipocyte differentiation; activin AB activates ALK7-SMAD3 signaling in brown preadipocytes to suppress PPARgamma and differentiation, while ALK7 activation during late differentiation reduces lipid content but enhances UCP1 expression.\",\n      \"method\": \"Pharmacological and genetic tools in murine brown adipocytes, differentiation assays, SMAD3 signaling analysis, cGMP pathway modulation\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic/pharmacological interventions in relevant cell type with mechanistic pathway identification\",\n      \"pmids\": [\"26266090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ALK7 maintains cardiac repolarization by supporting expression of repolarizing K+ channels; Alk7-/- cardiomyocytes show reduced Ito and IK1 currents, decreased Kv4.2 and KCHIP2 expression, prolonged action potential duration, and increased ventricular arrhythmia susceptibility.\",\n      \"method\": \"Alk7 knockout mice, telemetry ECG, Langendorff perfusion, whole-cell patch clamp, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockout with electrophysiological and molecular mechanistic characterization\",\n      \"pmids\": [\"26882027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACVR1C/ALK7 signaling through SMAD2 (not SMAD3) promotes invasion, growth, and survival of retinoblastoma cells; pharmacological inhibition with SB505124 or shRNA knockdown suppresses invasion and reduces ZEB1/Snail mesenchymal markers. ALK7 knockdown reduces tumor spread in an orthotopic zebrafish model.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition, invasion assays, apoptosis assays, zebrafish orthotopic model, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary loss-of-function approaches (shRNA + pharmacological) with in vitro and in vivo validation\",\n      \"pmids\": [\"30401983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ALK7 activated by activin B induces apoptosis in neoplastic cells, acting as a tumor suppressor barrier; during tumorigenesis, cancer cells evade this by downregulating activin B and/or ALK7. Suppression of ALK7 enhances metastatic seeding in mouse models of pancreatic neuroendocrine and luminal breast cancer.\",\n      \"method\": \"Functional studies in mouse cancer models, experimental metastasis assays, ALK7 expression modulation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic models with mechanistic pathway (activin B-ALK7-apoptosis axis) validated in multiple cancer types\",\n      \"pmids\": [\"31063757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The activin-ALK7 pathway mediates endothelial ablation by pancreatic ductal adenocarcinoma; PDAC cells use ALK7 signaling to destroy endothelial cells in a 3D organotypic tumor-on-a-chip model and in vivo PDAC models, contributing to tumor hypovascularity.\",\n      \"method\": \"3D organotypic PDAC-on-a-chip model, in vivo PDAC models, pharmacological inhibition of ALK7\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel organotypic model with in vivo confirmation, pathway-specific inhibition\",\n      \"pmids\": [\"31489365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALK7 in brown adipose tissue limits catabolic responses to nutrient stress; BAT-specific ALK7 deletion causes fasting-induced hypothermia due to exaggerated catabolism, with increased KLF15, proline dehydrogenase (POX), and ATGL expression. ALK7 ligand stimulation suppresses POX and KLF15 in brown adipocytes. Glucocorticoid receptor antagonist (RU486) normalizes KLF15/POX in mutant BAT, implicating excessive glucocorticoid signaling.\",\n      \"method\": \"BAT-specific Alk7 conditional knockout, fasting/cold challenge, gene expression analysis, ligand stimulation of human brown adipocytes, RU486 pharmacological rescue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific knockout with multiple functional readouts and pharmacological rescue identifying downstream pathway\",\n      \"pmids\": [\"32366358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Activin E (INHBE) signals through ACVR1C to suppress beta-agonist-induced lipolysis in adipose tissue, activating SMAD2/3 signaling and suppressing PPARgamma target genes; loss of activin E or ACVR1C increases fat utilization and drives PPARgamma-regulated gene signatures indicative of healthy adipose function.\",\n      \"method\": \"Activin E and ACVR1C knockout mice, SMAD2/3 signaling assay, lipolysis assay, RNA-seq, ligand-receptor identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel ligand and receptor knockouts with mechanistic pathway (SMAD2/3, PPARgamma) validated by multiple methods\",\n      \"pmids\": [\"37523551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional ALK7 ablation in adipocytes synergizes with low-fat diet switch or anti-inflammatory treatment (Na-salicylate) to enhance lipolysis and energy expenditure; mechanistically, this combination strongly upregulates beta3-AR expression and its upstream regulator C/EBPalpha.\",\n      \"method\": \"Conditional adipocyte-specific Alk7 knockout in obese mice, pharmacological treatment, beta3-AR/C/EBPalpha expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with mechanistic pathway (beta3-AR/C/EBPalpha) in relevant physiological context\",\n      \"pmids\": [\"34245608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACVR1C signaling through SMAD2 phosphorylation regulates SREBP1 and ACC expression in keratinocytes; UV irradiation decreases ACVR1C and epidermal triglyceride synthesis, effects modulated by ACVR1C knockdown or overexpression.\",\n      \"method\": \"shRNA knockdown and overexpression, UV irradiation, Western blot for pSMAD2, lipogenic gene expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional gain/loss-of-function with SMAD2 pathway connection, single lab\",\n      \"pmids\": [\"33499275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ACVR1C missense variants (I195T, I482V, N150H) have graded effects on ALK7 signaling and metabolic phenotype in knock-in mice: I195T phenocopies null mutants (impaired ALK7 signaling, HFD-obesity resistance, enhanced lipolysis); I482V shows partial phenotype; N150H is metabolically indistinguishable from wild type at normal ligand concentrations but shows reduced signaling at low ligand levels.\",\n      \"method\": \"Knock-in mouse models for each human variant, high-fat diet challenge, ALK7 signaling assays, lipolysis assays, fat mass measurement\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — three independent knock-in alleles with mechanistic ALK7 signaling characterization, connecting human variants to function\",\n      \"pmids\": [\"38307384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR1C expression is epigenetically regulated at its promoter by exercise (alleviating repression); ACVR1C activation suppresses Mkrn3 via Smad2/3 signaling, involving KAP1 recruitment and repressive histone modifications. ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice; overexpression of Acvr1c enables learning in aged/5xFAD mice.\",\n      \"method\": \"RNA-seq of dorsal hippocampus, epigenetic analysis (ChIP), Acvr1c overexpression in mice, synaptic plasticity assays, memory behavior tests\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (ChIP, behavior, electrophysiology) but novel context (memory/hippocampus) from single lab\",\n      \"pmids\": [\"38714691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Acvr1c activation suppresses Mkrn3 expression via Smad2/3 signaling with KAP1 recruitment and repressive histone modifications at the Mkrn3 locus, providing a mechanism for pubertal timing regulation.\",\n      \"method\": \"RNA-seq correlation analysis, experimental validation of Acvr1c activation, ChIP for KAP1 and histone marks, Smad2/3 signaling assays\",\n      \"journal\": \"NAR molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic ChIP and signaling validation, single study\",\n      \"pmids\": [\"41255711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In pancreatic cancer, ALK7 drives metastasis through two non-canonical pathways: ALK7-beta-catenin-EMT (enhancing tumor cell motility) and ALK7-beta-catenin-MMP (upregulating MMPs, ECM degradation, invadosome formation, vascular basement membrane breakdown, and intravasation). Both pharmacological and genetic ALK7 inhibition suppress metastasis in orthotopic models and 3D microfluidic vessel-on-chip platforms.\",\n      \"method\": \"Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic knockdown/knockout, pharmacological inhibition, MMP inhibition, beta-catenin pathway analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems and pathway validation, single lab but comprehensive\",\n      \"pmids\": [\"40616087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GREM1 binds ACVR1C as a novel high-affinity epithelial receptor, activating SMAD2/3 signaling which upregulates SNAI1 and GREM1 itself, establishing a positive feedback autocrine loop that sustains EMT and promotes colorectal cancer metastasis.\",\n      \"method\": \"Binding assays identifying ACVR1C as GREM1 receptor, SMAD2/3 signaling assays, in vivo metastasis models, feedback loop characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel receptor-ligand identification with downstream pathway and in vivo validation, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\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 (ActRIIA/B) and co-receptors (Cripto) to transduce signals from Nodal, activin B, activin AB, GDF3, and activin E (INHBE), primarily through phosphorylation and nuclear translocation of Smad2/3, which regulate transcriptional programs controlling adipose lipolysis, energy homeostasis, pancreatic beta-cell insulin secretion, neuronal differentiation, trophoblast invasion, cardiac function, and tumor suppression/metastasis depending on cell context.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACVR1C (ALK7) is a type I serine/threonine kinase receptor of the TGF-β superfamily that transduces signals from multiple ligands—Nodal, activin B, activin AB, GDF3, and activin E (INHBE)—through phosphorylation of Smad2/3 to regulate diverse processes including adipose metabolism, pancreatic β-cell function, neuronal differentiation, cardiac homeostasis, reproductive neuroendocrine circuits, and tumor suppression. In adipose tissue, ALK7 suppresses β-adrenergic receptor expression and lipolysis, and its genetic ablation confers resistance to diet-induced obesity and enhances energy expenditure by upregulating β3-AR/C/EBPα and mitochondrial biogenesis [PMID:25161195, PMID:37523551, PMID:38307384]. In pancreatic β-cells, activin B–ALK7 signaling negatively regulates glucose-stimulated insulin secretion through modulation of Ca²⁺ influx, while Nodal–ALK7 signaling induces apoptosis via Smad2/3-dependent caspase-3 activation and Akt/XIAP suppression [PMID:18480258, PMID:22550067]. ALK7 also functions as a tumor suppressor barrier—activin B–ALK7 induces apoptosis in neoplastic cells, and cancer cells evade this by downregulating ALK7 or its ligands—though in pancreatic ductal adenocarcinoma ALK7 can paradoxically promote metastasis through non-canonical β-catenin–MMP pathways [PMID:31063757, PMID:40616087].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The first mechanistic evidence that ALK7 signals through the Smad pathway was established when constitutively active ALK7 was shown to activate Smad2 and Smad3 (but not Smad1) and drive their nuclear translocation, defining ALK7 as an activin/TGF-β-branch type I receptor.\",\n      \"evidence\": \"Constitutively active ALK7 transfection with chimeric Smad constructs, nuclear translocation assays, and PAI-1 promoter-reporter in cell lines\",\n      \"pmids\": [\"9920806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without identification of the endogenous ligand\", \"Domain requirements for Smad2 vs Smad3 activation not independently validated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"ALK7 was shown to have pleiotropic cellular effects beyond Smad activation—inducing growth arrest (via p15INK4B/p21), ERK/JNK activation, and neuronal differentiation—establishing it as a multifunctional signaling receptor.\",\n      \"evidence\": \"Tetracycline-inducible constitutively active ALK7 in PC12 cells with proliferation, reporter, and morphological assays\",\n      \"pmids\": [\"11084022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand for ALK7 in neuronal cells not identified\", \"ERK/JNK activation mechanism (direct vs indirect) unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The identity of ALK7's physiological ligand was resolved when Nodal was shown to signal through an ALK7/ActRIIB complex, with the co-receptor Cripto greatly enhancing responsiveness, explaining how Nodal achieves cell-type-specific signaling.\",\n      \"evidence\": \"Receptor reconstitution, dominant-negative and constitutively active constructs in Xenopus embryos, binding assays\",\n      \"pmids\": [\"11485994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ALK7 has Nodal-independent ligands was unknown\", \"Structural basis of Cripto-ALK7 interaction unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Development of selective small-molecule inhibitors (SB-431542) that block ALK4/5/7 kinase activity provided pharmacological tools confirming ALK7's kinase-dependent signaling mechanism and enabling pathway dissection.\",\n      \"evidence\": \"In vitro kinase assay and cell-based signaling assays with extensive selectivity profiling\",\n      \"pmids\": [\"12065756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SB-431542 cannot distinguish ALK7 from ALK4/ALK5 effects\", \"No ALK7-selective inhibitor developed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The ligand repertoire of ALK7 was expanded beyond Nodal when activin B and activin AB were identified as ALK7 ligands that preferentially pair with ActRIIA (not ActRIIB), and this combination was shown to regulate insulin secretion in β-cells—establishing ALK7's metabolic role.\",\n      \"evidence\": \"Receptor reconstitution in cell lines with insulin secretion functional readout; parallel Nodal-ALK7 apoptosis studies in trophoblast\",\n      \"pmids\": [\"15196700\", \"15150278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of activin B–ALK7 axis in β-cells pending\", \"Downstream mechanism linking ALK7 to insulin exocytosis machinery unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"ALK7 knockout mice developed normally without left-right patterning defects, demonstrating that ALK7 is dispensable for canonical Nodal functions in embryogenesis and redirecting the field toward tissue-specific metabolic and neurological roles.\",\n      \"evidence\": \"Global ALK7 knockout mouse generation with comprehensive histological and compound mutant analysis\",\n      \"pmids\": [\"15485907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolic phenotypes of knockout not yet characterized\", \"Compensatory mechanisms by ALK4 not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic epistasis with activin B and ALK7 double knockouts proved they function in a common pathway to negatively regulate glucose-stimulated insulin secretion through Ca²⁺ signaling, while parallel studies showed GDF3 signals through ALK7/Cripto to regulate adipose accumulation.\",\n      \"evidence\": \"Single and double knockout mice with calcium imaging, insulin secretion, and high-fat diet metabolic phenotyping\",\n      \"pmids\": [\"18480258\", \"18480259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ALK7-Smad and Ca²⁺ channel regulation not identified\", \"Relative contributions of activin B vs GDF3 in adipose tissue unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The central adipose mechanism was established: ALK7 mediates diet-induced catecholamine resistance by suppressing β-adrenergic receptor expression and lipolysis cell-autonomously, and acute chemical-genetic inhibition recapitulated genetic ablation effects, validating ALK7 as a druggable anti-obesity target.\",\n      \"evidence\": \"Global and adipose-specific Alk7 knockout, chemical-genetic acute inhibition, β-AR signaling and lipolysis assays in mouse and human adipocytes\",\n      \"pmids\": [\"25161195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Smad2/3 suppresses β-AR transcription not defined\", \"Human genetic validation lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ALK7 was shown to protect against pathological cardiac hypertrophy through MEK-ERK1/2 inhibition, and separately to regulate brown adipocyte differentiation via Smad3-PPARγ signaling, revealing tissue-specific non-canonical pathway usage.\",\n      \"evidence\": \"Cardiac-specific transgenic and knockout mice with aortic banding; brown adipocyte differentiation assays with pharmacological/genetic tools\",\n      \"pmids\": [\"26249805\", \"26266090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab cardiac studies await independent replication\", \"Whether ALK7 directly inhibits MEK-ERK or acts through an intermediate not resolved\", \"Brown adipocyte findings not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ALK7 was established as a tumor suppressor: activin B–ALK7 induces apoptosis as a barrier to metastatic seeding, and cancer cells evade this by downregulating ALK7 or activin B—while paradoxically, in PDAC, ALK7 signaling destroys endothelial cells contributing to tumor hypovascularity.\",\n      \"evidence\": \"In vivo mouse models of pancreatic neuroendocrine cancer, luminal breast cancer, and PDAC with genetic ALK7 modulation and organotypic tumor-on-a-chip\",\n      \"pmids\": [\"31063757\", \"31489365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependent switch from tumor suppressor to pro-metastatic signaling unexplained mechanistically\", \"Patient-derived tumor ALK7 expression patterns not systematically characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Activin E (INHBE) was identified as a new ALK7 ligand that suppresses lipolysis via Smad2/3 and PPARγ target gene repression, while separately ALK7 was shown to regulate Mkrn3 expression through Smad2/3-KAP1 epigenetic repression, expanding ALK7's roles to include pubertal timing and epigenetic regulation.\",\n      \"evidence\": \"Parallel activin E and ACVR1C knockout mice with RNA-seq and lipolysis assays; ChIP for KAP1 and histone marks at Mkrn3 locus\",\n      \"pmids\": [\"37523551\", \"34245608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether INHBE is the primary ALK7 ligand in human adipose unknown\", \"Mkrn3 regulation validated only in mouse hippocampus, relevance to human puberty not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Human genetic variants in ACVR1C were functionally validated through knock-in mice, showing graded allelic effects on ALK7 signaling and metabolic phenotype—I195T phenocopies null (obesity resistance), I482V is partial, N150H is near-normal—directly connecting human sequence variation to receptor function.\",\n      \"evidence\": \"Three independent knock-in mouse models with high-fat diet challenge, ALK7 signaling quantification, and lipolysis assays\",\n      \"pmids\": [\"38307384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human population-level metabolic phenotyping of carriers not completed\", \"Structural basis for graded signaling defects not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ALK7 was linked to synaptic plasticity and memory: hippocampal Acvr1c overexpression rescued learning deficits in aged and 5xFAD Alzheimer's model mice, with exercise alleviating epigenetic repression at the Acvr1c promoter.\",\n      \"evidence\": \"RNA-seq of dorsal hippocampus, epigenetic analysis, Acvr1c overexpression, electrophysiology, and behavioral memory tests in mice\",\n      \"pmids\": [\"38714691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding in novel context requires independent replication\", \"Endogenous ALK7 ligand in hippocampus not identified\", \"Mechanism linking Smad signaling to synaptic plasticity genes undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In pancreatic cancer, ALK7 was shown to drive metastasis through non-canonical β-catenin–EMT and β-catenin–MMP pathways promoting intravasation, redefining ALK7 as context-dependently pro-metastatic rather than purely tumor-suppressive.\",\n      \"evidence\": \"Orthotopic PDAC mouse model, 3D microfluidic vessel-on-chip, genetic and pharmacological ALK7 inhibition, β-catenin/MMP pathway analysis\",\n      \"pmids\": [\"40616087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; non-canonical β-catenin pathway not validated independently\", \"How ALK7 switches from canonical Smad to non-canonical β-catenin signaling unknown\", \"Therapeutic window for ALK7 inhibition in cancer vs metabolic disease unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis of ALK7 ligand selectivity and co-receptor requirement, (2) the molecular switch between canonical Smad and non-canonical (β-catenin, ERK) pathway engagement, (3) whether ALK7 can be selectively targeted therapeutically given shared inhibitor sensitivity with ALK4/ALK5, and (4) the identity and role of ALK7 ligands in the CNS.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of ALK7 with any ligand\", \"No ALK7-selective small molecule inhibitor reported\", \"CNS ligand identity unknown\", \"Patient stratification criteria for ALK7-targeted therapy undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 16, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 2, 3, 6, 11, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 15, 23, 24, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 13, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 21, 30]}\n    ],\n    \"complexes\": [\n      \"ALK7/ActRIIB\",\n      \"ALK7/ActRIIA\"\n    ],\n    \"partners\": [\n      \"ACVR2A\",\n      \"ACVR2B\",\n      \"TDGF1\",\n      \"SMAD2\",\n      \"SMAD3\",\n      \"NODAL\",\n      \"INHBB\",\n      \"INHBE\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}