{"gene":"CRTC1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2005,"finding":"The MECT1-MAML2 (CRTC1-MAML2) fusion protein binds to CREB via the N-terminal CREB-binding domain of MECT1/CRTC1, recruits p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activates CREB-dependent transcription. Blocking CREB DNA binding markedly reduced the transforming activity of the fusion protein.","method":"Co-immunoprecipitation, reporter gene assays, dominant-negative CREB mutants, gene expression profiling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating CREB binding, functional rescue with dominant-negative mutants, replicated by multiple orthogonal methods in one rigorous study","pmids":["15961999"],"is_preprint":false},{"year":2005,"finding":"Small in-frame deletions within the CREB-binding domain of MECT1/CRTC1 completely abolished the transforming activity of the Mect1-Maml2 fusion oncogene in RK3E epithelial cells, establishing that CRTC1's CREB-binding domain is essential for oncogenic function. The fusion activates known cAMP/CREB-regulated genes but does not alter Notch-regulated target genes.","method":"Deletion mutagenesis, RK3E transformation assay, doxycycline-inducible expression system, microarray gene expression profiling, RT-PCR validation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — deletion mutagenesis combined with in vitro transformation assay and gene expression profiling, replicated in multiple cell lines","pmids":["16103063"],"is_preprint":false},{"year":2009,"finding":"CRTC1 (TORC1) is required for activity-dependent CREB-target gene expression and dendritic growth in developing cortical neurons. Ca2+ influx via voltage-gated calcium channels induced CRTC1 dephosphorylation and nuclear translocation in a calcineurin-dependent manner. Nuclear CRTC1 initiated CREB-target gene expression including SIK1, which then phosphorylated CRTC1 to deplete it from the nucleus—a negative feedback loop limiting persistent CREB/CRTC1 transcription.","method":"Live-cell imaging, pharmacological inhibitors (calcineurin inhibitor FK506, L-type VGCC blockers), dominant-negative CRTC1, siRNA knockdown, immunofluorescence, in vivo overexpression","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pharmacology, dominant-negative, knockdown, in vivo), clear mechanistic pathway established with functional dendritic growth readout","pmids":["19244510"],"is_preprint":false},{"year":2009,"finding":"CRTC1 promotes cell proliferation and transformation via AP-1. After TPA stimulation, CRTC1 is recruited to AP-1 target gene promoters and physically associates with c-Jun and c-Fos to activate transcription. The CRTC1-MAML2 oncoprotein also binds and activates both c-Jun and c-Fos; ablation of AP-1 function disrupts cellular transformation and proliferation mediated by CRTC1-MAML2.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, siRNA knockdown, dominant-negative AP-1, reporter assays, colony formation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating promoter recruitment, Co-IP showing physical association with c-Jun/c-Fos, loss-of-function with defined transcriptional and proliferation phenotype","pmids":["19164581"],"is_preprint":false},{"year":2009,"finding":"Loss of LKB1 in lung cancer cells is associated with underphosphorylation of endogenous CRTC1 and enhanced CRTC1 nuclear localization, leading to elevated expression of the CRTC1 target gene NR4A2/Nurr1. Inhibition of NR4A2 suppressed growth of LKB1-null tumors, placing CRTC1 downstream of the LKB1 tumor-suppressor pathway.","method":"Western blotting (phospho-CRTC1), immunofluorescence (nuclear localization), siRNA knockdown of NR4A2, colony formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation and localization measurements in cell lines plus functional NR4A2 knockdown, single lab with two orthogonal approaches","pmids":["20010869"],"is_preprint":false},{"year":2010,"finding":"Beta-amyloid suppresses CRTC1-dependent gene transcription in Alzheimer's disease model neurons by reducing calcium influx through L-type voltage-gated calcium channels, thereby disrupting PP2B/calcineurin-dependent dephosphorylation of CRTC1 at Ser151. Expression of constitutively active CRTC1 S151A or calcineurin mutants reversed transcriptional deficits. CRTC1-dependent memory genes (Bdnf, c-fos, Nr4a2) were selectively reduced coinciding with spatial memory deficits.","method":"Pharmacological manipulation (L-VGCC agonists/antagonists, NMDA/AMPA receptor blockers), phosphorylation assays, luciferase reporter, immunofluorescence, transgenic APP mouse model, behavioral testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphosite-specific rescue experiments (S151A mutant) plus pharmacological dissection in multiple assay systems and in vivo correlation","pmids":["20631169"],"is_preprint":false},{"year":2013,"finding":"CRTC1 functions in the suprachiasmatic nucleus (SCN) to regulate circadian clock entrainment. Light pulses cause CRTC1 to co-activate CREB, inducing Per1 and SIK1 expression. SIK1 then phosphorylates and deactivates CRTC1, providing negative feedback to suppress further light-induced clock shifts. Knockdown of Sik1 in the SCN increased behavioral phase shifts and rapid re-entrainment after experimental jet lag.","method":"SCN transcriptome analysis, in vivo Sik1 knockdown (lentiviral shRNA), behavioral phase-shift assays, immunohistochemistry, reporter assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined behavioral readout, combined with transcriptomic and biochemical characterization, published in high-tier journal","pmids":["23993098"],"is_preprint":false},{"year":2013,"finding":"CRTC1 (TORC1) shows rhythmic expression in the SCN and undergoes light-induced nuclear accumulation specifically in early and late subjective night. ChIP analysis confirmed that CRTC1 associates with CREB at the 5′ regulatory region of the Period1 gene; overexpression of CRTC1 markedly upregulates Period1 transcription. CRTC2 does not show photic regulation of subcellular localization in the SCN.","method":"Immunohistochemistry, chromatin immunoprecipitation, reporter gene assay, light-pulse paradigm in mice","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating CRTC1 occupancy at Per1 promoter combined with gain-of-function and direct localization experiment, single lab","pmids":["23699513"],"is_preprint":false},{"year":2014,"finding":"CRTC1 nuclear translocation in hippocampal neurons is regulated by convergence of constitutive kinase pathways and the activity-regulated phosphatase calcineurin. Nuclear CRTC1 binds CREB at IEG promoters in an activity-dependent manner. Forced nuclear expression of CRTC1 in hippocampal neurons activated CREB-dependent transcription and enhanced contextual fear memory. During contextual fear conditioning, endogenous CRTC1 nuclear recruitment occurred in the basolateral amygdala but not hippocampus; CRTC1 knockdown in the amygdala (but not hippocampus) attenuated fear memory.","method":"Region-specific viral CRTC1 knockdown, ChIP, immunofluorescence, contextual fear conditioning behavioral assay, reporter assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — region-specific loss-of-function with defined behavioral phenotype, ChIP showing promoter occupancy, and gain-of-function, multiple orthogonal methods in one study","pmids":["25277455"],"is_preprint":false},{"year":2014,"finding":"CRTC1-MAML2 (C1/M2) oncoprotein gains a novel function by interacting with MYC proteins and activating MYC transcription targets involved in cell growth, metabolism, survival, and tumorigenesis. The C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation.","method":"Co-immunoprecipitation, reporter assays, gene expression profiling, transformation assay in human MEC tumor cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical interaction plus functional transformation assay with defined MYC dependency, single lab","pmids":["25071166"],"is_preprint":false},{"year":2014,"finding":"In the hippocampus of APPSw,Ind Alzheimer's disease model mice, synaptic activity and spatial memory training induce CRTC1 dephosphorylation at Ser151 and nuclear translocation, and these events are impaired at early pathological and cognitive decline stages. AAV-mediated Crtc1 overexpression in the hippocampus reversed Aβ-induced spatial memory deficits by restoring a specific subset of Crtc1 target genes.","method":"AAV-mediated gene delivery, phosphorylation immunoassays, immunohistochemistry, microarray transcriptomics, Morris water maze behavioral testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue experiment (AAV-Crtc1) with defined behavioral and transcriptional readouts, phosphosite-specific biochemical measurements, combined with disease model","pmids":["24760838"],"is_preprint":false},{"year":2015,"finding":"CRTC1 is activated by PGE2 signaling in colon cancer cells through EP1 and EP2 receptor-mediated calcineurin and PKA activation, leading to CRTC1 dephosphorylation and nuclear translocation with enhanced CRTC1 transcriptional activity. CRTC1 loss of function reduced viability and cell division; stable CRTC1 overexpression increased xenograft tumor growth. CRTC1-activated genes including NR4A2, COX2, AREG and IL-6 depend on functional AP1 and CREB partners.","method":"Pharmacological receptor antagonists, calcineurin inhibitors, PKA modulators, phosphorylation assays, immunofluorescence, siRNA knockdown, stable overexpression, xenograft model, reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway dissected pharmacologically and confirmed by loss/gain-of-function with multiple in vitro and in vivo readouts, single lab with multiple orthogonal methods","pmids":["26300003"],"is_preprint":false},{"year":2016,"finding":"CRTC1 knockdown in hippocampal neurons impairs associative memory. Context-associative learning (but not single context or unconditioned stimuli alone) induces rapid dephosphorylation of CRTC1 at Ser151 and translocation from cytosol/dendrites to the nucleus, driving expression of c-fos and Nr4a1-3. This CRTC1 activation is disrupted in presenilin conditional double-knockout (neurodegeneration) mice. AAV-mediated CRTC1 gene therapy in the hippocampus ameliorated memory, transcriptional deficits and dendritic degeneration.","method":"One-trial contextual fear conditioning, phosphorylation assays, immunohistochemistry, ChIP, gene expression analysis, AAV gene therapy, presenilin cDKO mouse model","journal":"Biological psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function and rescue with defined behavioral and transcriptional phenotypes, phosphosite-specific biochemistry, ChIP showing promoter occupancy","pmids":["27587263"],"is_preprint":false},{"year":2017,"finding":"CRTC1 mediates preferential activity-dependent transcription at neuronal CRE/TATA-containing promoters. Neuronal activity and cAMP signals induce CRTC1 dephosphorylation, nuclear translocation, and activity-dependent binding to endogenous CREB; recruitment of CRTC1 to CRE/TATA promoters (c-fos, Dusp1, Nr4a1, Nr4a2, Ptgs2) is activity-dependent, whereas CREB itself is constitutively bound. Genes with CRE/TATA-less promoters are not induced.","method":"Chromatin immunoprecipitation, phosphorylation assays, immunofluorescence, luciferase reporter assays, neuronal depolarization/cAMP stimulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating activity-dependent CRTC1 recruitment to specific promoters combined with phosphorylation and reporter assays, single lab","pmids":["29269871"],"is_preprint":false},{"year":2018,"finding":"CRTC1-MAML2 fusion protein induces expression of LINC00473 lncRNA through CREB-mediated transcription, and this depends on the CRTC1-MAML2 ability to activate CREB. LINC00473 is required for MEC cell proliferation and survival in vitro and in vivo. LINC00473 binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-driven CREB-mediated transcription.","method":"Lentiviral shRNA knockdown, xenograft tumor model, RNA immunoprecipitation (NONO binding), gene expression profiling, RNA ISH","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined proliferation/survival phenotype, RNA-protein interaction assay, single lab","pmids":["29353885"],"is_preprint":false},{"year":2019,"finding":"SIK1 phosphorylates CRTC1, preventing CRTC1 from enhancing CREB transcriptional activity for the expression of osteogenic genes such as Id1. BMP2 suppresses both SIK1 expression and SIK1 activity through PKA-dependent mechanisms to stimulate osteogenesis. SIK1 knockout mice display higher bone mass, osteoblast number, and bone formation rate.","method":"SIK1 kinase activity assay, SIK1 knockdown/knockout mice, osteoblast differentiation assays, bone mineralization assays, PKA inhibitor studies, phosphorylation assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct kinase assay combined with in vivo knockout phenotype and defined molecular pathway (SIK1→CRTC1→CREB→Id1), multiple orthogonal methods","pmids":["31672960"],"is_preprint":false},{"year":2021,"finding":"CRTC1-MAML2 is the major oncogenic driver of mucoepidermoid carcinoma (MEC). Doxycycline-induced knockdown of CRTC1-MAML2 blocked growth of established MEC xenografts. Conditional transgenic expression of CRTC1-MAML2 in mice caused 100% penetrant salivary gland tumor formation resembling human MEC histology. CRTC1-MAML2 activates AREG/EGFR signaling; combined CDK4/6 (Palbociclib) and EGFR (Erlotinib) inhibition produced enhanced antitumor responses in vitro and in vivo.","method":"Doxycycline-inducible shRNA knockdown, conditional transgenic mouse model, xenograft growth assays, molecular pathway analysis, combination drug treatment in vitro and in vivo","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional transgenic mouse model and in vivo knockdown both demonstrating oncogenic driver role, with defined molecular pathway, multiple orthogonal approaches","pmids":["33830080"],"is_preprint":false},{"year":2021,"finding":"CRTC1-MAML2 directs transcriptional activation of PGC-1α4 (a non-canonical splice variant), which regulates PPARγ-mediated IGF-1 expression. This autocrine IGF-1 circuit renders MEC cells selectively sensitive to IGF-1R inhibition and PPARγ inverse agonism.","method":"Gene expression profiling, small-molecule drug screens, reporter assays, IGF-1R inhibitor treatment, PPARγ inhibitor treatment, primary tumor molecular analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene expression and functional drug sensitivity data with mechanistic pathway (C1/M2→PGC-1α4→PPARγ→IGF-1), single lab, multiple orthogonal methods","pmids":["33626346"],"is_preprint":false},{"year":2021,"finding":"NMDAR activation in neurons induces dephosphorylation of CRTC1 at Ser151 and nuclear translocation, where CRTC1 competes with FXR for binding to CREB and drives autophagy gene expression required for late-phase long-term synaptic depression (L-LTD). Disrupting CRTC1-CREB interaction impaired transcription-dependent autophagy and prevented NMDAR-dependent L-LTD.","method":"Phosphorylation assays, immunofluorescence, co-immunoprecipitation (CRTC1-CREB, CRTC1-FXR competition), shRNA knockdown, electrophysiology (LTD recordings), autophagy assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing competition between CRTC1 and FXR for CREB binding, combined with loss-of-function electrophysiology readout, single lab","pmids":["34289350"],"is_preprint":false},{"year":2022,"finding":"VDAC1 depletion increases free cytosolic Ca2+ in melanocytes, activating calcineurin through the Ca2+-calmodulin-calcineurin pathway, which dephosphorylates CRTC1 to facilitate its nuclear translocation and upregulate MITF transcription, increasing melanogenic gene expression (TYR, TYRP1, TYRP2).","method":"VDAC1 siRNA knockdown, Ca2+ imaging, calcineurin activity assay, CRTC1 phosphorylation assays, nuclear fractionation/immunofluorescence, reporter assays, VDAC1 knockout mice","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (VDAC1→Ca2+→calcineurin→CRTC1 dephosphorylation→nuclear translocation→MITF) established with multiple biochemical methods plus in vivo mouse confirmation, single lab","pmids":["35649693"],"is_preprint":false},{"year":2022,"finding":"miR-184-3p directly targets CRTC1 mRNA; downregulation of miR-184-3p in human T2D pancreatic islets leads to upregulation of CRTC1, which protects β-cells from lipotoxicity- and inflammation-induced apoptosis. The protective effect of miR-184-3p inhibition is CRTC1-dependent, as CRTC1 silencing abrogates it. NKX6.1 directly controls miR-184 expression via binding sites in the MIR184 promoter.","method":"Chromatin immunoprecipitation (NKX6.1 binding to MIR184 promoter), mRNA and protein expression assays, CRTC1 siRNA silencing, luciferase miRNA target validation, apoptosis assays in human β-cells","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming NKX6.1 binding, validated miRNA-target interaction, loss-of-function showing CRTC1-dependency of protective phenotype, single lab","pmids":["35906204"],"is_preprint":false},{"year":2006,"finding":"Sustained expression of Mect1-Maml2 (CRTC1-MAML2) is required for MEC tumor cell growth. RNAi-mediated suppression of the fusion oncogene in parotid and pulmonary MEC cell lines with t(11;19) caused ≥90% colony growth inhibition, which could be partially rescued by co-expressing an RNAi-resistant Mect1-Maml2 mutant. Non-MEC tumor lines lacking the fusion were unaffected.","method":"shRNA knockdown, colony formation assay, rescue with RNAi-resistant mutant, in vivo nude mouse xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — selective knockdown with specific rescue experiment confirming on-target effect, in vivo xenograft validation, multiple cell line controls","pmids":["16652146"],"is_preprint":false}],"current_model":"CRTC1 is a CREB transcriptional coactivator that is held in the cytoplasm by phosphorylation (primarily at Ser151 by SIK-family kinases including SIK1 and SIK2) and translocates to the nucleus upon dephosphorylation by calcineurin downstream of Ca2+ and cAMP signals, where it binds CREB and preferentially activates CRE/TATA-containing gene promoters (including Per1, c-fos, Nr4a genes, and BDNF); SIK1 is itself a CREB/CRTC1 target gene that provides negative feedback by re-phosphorylating CRTC1; this pathway regulates circadian entrainment, memory consolidation, dendritic growth, osteoblast differentiation, and melanogenesis; chromosomal t(11;19) translocation fuses the CREB-binding domain of CRTC1 to MAML2, creating a constitutively active CREB coactivator that also engages c-Jun/c-Fos (AP-1), MYC, and PGC-1α/PPARγ/IGF-1 circuits to drive mucoepidermoid carcinoma initiation and maintenance."},"narrative":{"mechanistic_narrative":"CRTC1 is a calcium- and cAMP-responsive transcriptional coactivator for CREB that converts neuronal and hormonal signals into activity-dependent gene programs [PMID:19244510, PMID:29269871]. In the resting state it is held in the cytoplasm by phosphorylation at Ser151 by SIK-family kinases, and Ca2+ influx through L-type voltage-gated calcium channels triggers calcineurin (PP2B)-dependent dephosphorylation, nuclear translocation, and activity-dependent binding to constitutively promoter-bound CREB, where CRTC1 is selectively recruited to CRE/TATA-containing promoters to induce immediate-early and effector genes such as c-fos, Nr4a1-3, Dusp1, Ptgs2, Per1 and Bdnf [PMID:19244510, PMID:20631169, PMID:29269871]. The coactivator is embedded in a self-limiting circuit: among its induced targets is SIK1, which re-phosphorylates CRTC1 to deplete it from the nucleus and terminate transcription [PMID:19244510, PMID:23993098]. Through this switch CRTC1 governs circadian clock entrainment in the suprachiasmatic nucleus via light-induced Per1 induction [PMID:23993098, PMID:23699513], drives dendritic growth and associative/fear memory consolidation in cortical, hippocampal and amygdalar neurons [PMID:19244510, PMID:25277455, PMID:27587263], and supports SIK1-regulated osteoblast differentiation and the calcineurin-MITF melanogenic program [PMID:31672960, PMID:35649693]. CRTC1 signaling is corrupted in disease: amyloid-beta blunts L-VGCC/calcineurin-driven CRTC1 dephosphorylation to suppress memory genes in Alzheimer's models, and restoring CRTC1 reverses these transcriptional and behavioral deficits [PMID:20631169, PMID:24760838, PMID:27587263]. The t(11;19) translocation fuses the N-terminal CREB-binding domain of CRTC1 to MAML2, generating a constitutively active coactivator that recruits p300/CBP to CREB and is the principal oncogenic driver of mucoepidermoid carcinoma, producing fully penetrant salivary gland tumors in mice [PMID:15961999, PMID:16103063, PMID:33830080]; the fusion's CREB-binding domain is strictly required for transformation [PMID:16103063, PMID:16652146], and it additionally co-opts AP-1 (c-Jun/c-Fos), MYC, LINC00473/NONO, and PGC-1α/PPARγ-IGF-1 and AREG/EGFR circuits to sustain tumor growth [PMID:19164581, PMID:25071166, PMID:29353885, PMID:33830080, PMID:33626346].","teleology":[{"year":2005,"claim":"Established that the CRTC1-MAML2 fusion transforms cells by acting as a constitutive CREB coactivator, defining the oncogenic mechanism and CRTC1's intrinsic CREB-binding function.","evidence":"Co-IP, reporter assays and dominant-negative CREB rescue plus deletion mutagenesis in RK3E transformation assays","pmids":["15961999","16103063"],"confidence":"High","gaps":["Did not define the endogenous regulatory inputs controlling wild-type CRTC1","Structural basis of CRTC1 CREB-binding domain interaction not resolved"]},{"year":2006,"claim":"Showed the fusion is continuously required for tumor maintenance, not merely initiation, validating it as a therapeutic dependency.","evidence":"shRNA knockdown with RNAi-resistant rescue in t(11;19) MEC lines and nude mouse xenografts","pmids":["16652146"],"confidence":"High","gaps":["Did not identify downstream effector genes responsible for growth dependency"]},{"year":2009,"claim":"Defined the physiological activation switch: Ca2+/calcineurin-dependent dephosphorylation drives nuclear CRTC1 to support CREB-target genes and dendritic growth, with SIK1 forming a negative feedback loop.","evidence":"Live imaging, calcineurin/VGCC pharmacology, dominant-negative and siRNA in cortical neurons","pmids":["19244510"],"confidence":"High","gaps":["Identity of the constitutive kinase(s) maintaining basal Ser151 phosphorylation not fully resolved","Did not establish promoter selectivity rules"]},{"year":2009,"claim":"Extended CRTC1's partner repertoire beyond CREB to AP-1, showing physical association with c-Jun/c-Fos drives both normal proliferation and fusion-driven transformation.","evidence":"ChIP, Co-IP, dominant-negative AP-1 and colony formation assays","pmids":["19164581"],"confidence":"High","gaps":["Mechanism of CRTC1 recruitment to AP-1 promoters not defined","Relative contribution of CREB vs AP-1 in transformation unquantified"]},{"year":2009,"claim":"Placed CRTC1 downstream of the LKB1 tumor suppressor, where LKB1 loss underphosphorylates CRTC1 and elevates the NR4A2 target to support tumor growth.","evidence":"Phospho-CRTC1 Western blot, immunofluorescence and NR4A2 siRNA in LKB1-null lung cancer cells","pmids":["20010869"],"confidence":"Medium","gaps":["Did not establish whether SIK-family kinases mediate the LKB1-CRTC1 link directly","Single-lab, two-approach support"]},{"year":2010,"claim":"Linked CRTC1 dysfunction to disease by showing amyloid-beta suppresses CRTC1 transcription via reduced L-VGCC Ca2+ influx and impaired Ser151 dephosphorylation, with S151A rescue.","evidence":"Phosphosite mutant rescue, L-VGCC pharmacology and behavior in APP transgenic mice","pmids":["20631169"],"confidence":"High","gaps":["Did not establish causality between specific target genes and memory rescue"]},{"year":2013,"claim":"Demonstrated CRTC1's role in circadian entrainment, where light-driven CRTC1-CREB induction of Per1 and SIK1 creates feedback limiting phase shifts in the SCN.","evidence":"SCN transcriptomics, in vivo Sik1 knockdown, ChIP at Per1, and behavioral phase-shift/jet-lag assays","pmids":["23993098","23699513"],"confidence":"High","gaps":["CRTC1-specific (vs CRTC2) requirement for entrainment not tested by loss-of-function","Per1 ChIP shows occupancy but not direct functional necessity"]},{"year":2014,"claim":"Mapped region-specific behavioral roles, showing CRTC1 nuclear recruitment in the amygdala (not hippocampus) is required for fear memory, and AAV-CRTC1 rescues Alzheimer-model deficits.","evidence":"Region-specific viral knockdown, ChIP, AAV rescue and fear/water-maze behavior in mouse models","pmids":["25277455","24760838"],"confidence":"High","gaps":["Basis of brain-region-specific CRTC1 activation not explained","Which target-gene subset mediates rescue incompletely defined"]},{"year":2014,"claim":"Identified MYC as a new fusion partner, with the CRTC1-MAML2-MYC interaction required for transformation, broadening the oncogenic transcriptional output.","evidence":"Co-IP, reporter and gene expression profiling with transformation assays in human MEC cells","pmids":["25071166"],"confidence":"Medium","gaps":["Direct vs indirect nature of the MYC interaction not resolved","Single lab"]},{"year":2015,"claim":"Established CRTC1 as an effector of PGE2/EP receptor signaling in colon cancer, where calcineurin/PKA-driven dephosphorylation activates proliferative and inflammatory target genes.","evidence":"Receptor antagonist/PKA/calcineurin pharmacology, loss/gain-of-function and xenografts","pmids":["26300003"],"confidence":"High","gaps":["Relative requirement of AP-1 vs CREB partners for each target gene not dissected"]},{"year":2016,"claim":"Refined the learning-specificity of CRTC1, showing context-association (not stimuli alone) triggers Ser151 dephosphorylation and nuclear translocation driving IEGs, with gene therapy rescuing degeneration.","evidence":"One-trial fear conditioning, phospho-assays, ChIP, AAV gene therapy in presenilin cDKO mice","pmids":["27587263"],"confidence":"High","gaps":["Upstream signal distinguishing association from single stimuli unknown"]},{"year":2017,"claim":"Defined the promoter-selectivity rule: activity-dependent CRTC1 recruitment occurs specifically at CRE/TATA promoters while CREB is constitutively bound, explaining gene-selective induction.","evidence":"ChIP across CRE/TATA vs CRE/TATA-less promoters with phospho and reporter assays in stimulated neurons","pmids":["29269871"],"confidence":"Medium","gaps":["Mechanism by which TATA element confers CRTC1 dependence unresolved","Single lab"]},{"year":2018,"claim":"Identified LINC00473/NONO as a downstream effector and feed-forward amplifier of fusion-driven CREB transcription required for MEC survival.","evidence":"shRNA knockdown, xenografts, RNA-IP for NONO and expression profiling","pmids":["29353885"],"confidence":"Medium","gaps":["Mechanism of LINC00473-NONO enhancement of CREB transcription not fully defined"]},{"year":2019,"claim":"Confirmed direct SIK1-CRTC1 regulation in a non-neural context, where SIK1 phosphorylation of CRTC1 restrains CREB-driven osteogenic genes like Id1.","evidence":"SIK1 kinase assay, SIK1 knockout mice, osteoblast differentiation and PKA inhibitor studies","pmids":["31672960"],"confidence":"High","gaps":["Whether Ser151 is the relevant SIK1 site in osteoblasts not specified"]},{"year":2021,"claim":"Consolidated CRTC1-MAML2 as the major MEC driver and revealed actionable AREG/EGFR, PGC-1α4/PPARγ-IGF-1 circuits enabling combination therapy.","evidence":"Conditional transgenic mouse, inducible knockdown, drug screens and combination treatment in vitro/in vivo","pmids":["33830080","33626346"],"confidence":"High","gaps":["PGC-1α4/IGF-1 arm is Medium-confidence single-lab","Direct vs indirect target relationships not fully mapped"]},{"year":2021,"claim":"Uncovered a transcription-coupled autophagy role, where NMDAR-driven CRTC1 competes with FXR for CREB to induce autophagy genes needed for late-phase LTD.","evidence":"Co-IP competition, phospho-assays, shRNA and LTD electrophysiology","pmids":["34289350"],"confidence":"Medium","gaps":["Structural basis of CRTC1/FXR competition not resolved","Single lab"]},{"year":2022,"claim":"Extended the Ca2+/calcineurin-CRTC1 axis to melanogenesis (VDAC1->Ca2+->MITF) and to beta-cell survival via miR-184-3p targeting of CRTC1 mRNA.","evidence":"VDAC1 knockdown/KO, Ca2+ imaging, calcineurin assays, miRNA target validation and apoptosis assays","pmids":["35649693","35906204"],"confidence":"Medium","gaps":["Direct MITF promoter occupancy by CRTC1 not shown","miR-184-3p/CRTC1 protective targets in beta-cells not enumerated"]},{"year":null,"claim":"The structural basis of CRTC1 promoter selectivity, the full set of kinases setting basal phosphorylation, and how cell-type context dictates which target programs CRTC1 activates remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CRTC1-CREB-CRE/TATA assembly","Determinants of tissue-specific target selection unknown","Mechanism linking distinct upstream signals to common CRTC1 dephosphorylation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,8,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[14,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,7,8,10,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,11,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,16,5]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]}],"complexes":["CRTC1-CREB coactivator complex"],"partners":["CREB","MAML2","CREBBP/EP300","JUN","FOS","MYC","SIK1","NONO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UUV9","full_name":"CREB-regulated transcription coactivator 1","aliases":["Mucoepidermoid carcinoma translocated protein 1","Transducer of regulated cAMP response element-binding protein 1","TORC-1","Transducer of CREB protein 1"],"length_aa":634,"mass_kda":67.3,"function":"Transcriptional coactivator for CREB1 which activates transcription through both consensus and variant cAMP response element (CRE) sites. Acts as a coactivator, in the SIK/TORC signaling pathway, being active when dephosphorylated and acts independently of CREB1 'Ser-133' phosphorylation. Enhances the interaction of CREB1 with TAF4. Regulates the expression of specific CREB-activated genes such as the steroidogenic gene, StAR. Potent coactivator of PGC1alpha and inducer of mitochondrial biogenesis in muscle cells. In the hippocampus, involved in late-phase long-term potentiation (L-LTP) maintenance at the Schaffer collateral-CA1 synapses. May be required for dendritic growth of developing cortical neurons (By similarity). In concert with SIK1, regulates the light-induced entrainment of the circadian clock. 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autophagy induction after DNA damage in budding yeast.","date":"2019","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/31201849","citation_count":16,"is_preprint":false},{"pmid":"29694832","id":"PMC_29694832","title":"Cdc14 Phosphatase Promotes TORC1-Regulated Autophagy in Yeast.","date":"2018","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29694832","citation_count":15,"is_preprint":false},{"pmid":"35649693","id":"PMC_35649693","title":"VDAC1 negatively regulates melanogenesis through the Ca2+-calcineurin-CRTC1-MITF pathway.","date":"2022","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/35649693","citation_count":14,"is_preprint":false},{"pmid":"29787763","id":"PMC_29787763","title":"The TORC1 signaling pathway regulates respiration-induced mitophagy in yeast.","date":"2018","source":"Biochemical and biophysical research 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prenatally stressed offspring rat.","date":"2020","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/33161032","citation_count":13,"is_preprint":false},{"pmid":"35205847","id":"PMC_35205847","title":"Slt2 Is Required to Activate ER-Stress-Protective Mechanisms through TORC1 Inhibition and Hexosamine Pathway Activation.","date":"2022","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35205847","citation_count":12,"is_preprint":false},{"pmid":"31712450","id":"PMC_31712450","title":"The TORC1 inhibitor Nprl2 protects age-related digestive function in Drosophila.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31712450","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48346,"output_tokens":6616,"usd":0.122139,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15453,"output_tokens":5316,"usd":0.105082,"stage2_stop_reason":"end_turn"},"total_usd":0.227221,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"The MECT1-MAML2 (CRTC1-MAML2) fusion protein binds to CREB via the N-terminal CREB-binding domain of MECT1/CRTC1, recruits p300/CBP into the CREB complex through a binding domain on MAML2, and constitutively activates CREB-dependent transcription. Blocking CREB DNA binding markedly reduced the transforming activity of the fusion protein.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, dominant-negative CREB mutants, gene expression profiling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating CREB binding, functional rescue with dominant-negative mutants, replicated by multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"15961999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Small in-frame deletions within the CREB-binding domain of MECT1/CRTC1 completely abolished the transforming activity of the Mect1-Maml2 fusion oncogene in RK3E epithelial cells, establishing that CRTC1's CREB-binding domain is essential for oncogenic function. The fusion activates known cAMP/CREB-regulated genes but does not alter Notch-regulated target genes.\",\n      \"method\": \"Deletion mutagenesis, RK3E transformation assay, doxycycline-inducible expression system, microarray gene expression profiling, RT-PCR validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — deletion mutagenesis combined with in vitro transformation assay and gene expression profiling, replicated in multiple cell lines\",\n      \"pmids\": [\"16103063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTC1 (TORC1) is required for activity-dependent CREB-target gene expression and dendritic growth in developing cortical neurons. Ca2+ influx via voltage-gated calcium channels induced CRTC1 dephosphorylation and nuclear translocation in a calcineurin-dependent manner. Nuclear CRTC1 initiated CREB-target gene expression including SIK1, which then phosphorylated CRTC1 to deplete it from the nucleus—a negative feedback loop limiting persistent CREB/CRTC1 transcription.\",\n      \"method\": \"Live-cell imaging, pharmacological inhibitors (calcineurin inhibitor FK506, L-type VGCC blockers), dominant-negative CRTC1, siRNA knockdown, immunofluorescence, in vivo overexpression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pharmacology, dominant-negative, knockdown, in vivo), clear mechanistic pathway established with functional dendritic growth readout\",\n      \"pmids\": [\"19244510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRTC1 promotes cell proliferation and transformation via AP-1. After TPA stimulation, CRTC1 is recruited to AP-1 target gene promoters and physically associates with c-Jun and c-Fos to activate transcription. The CRTC1-MAML2 oncoprotein also binds and activates both c-Jun and c-Fos; ablation of AP-1 function disrupts cellular transformation and proliferation mediated by CRTC1-MAML2.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, siRNA knockdown, dominant-negative AP-1, reporter assays, colony formation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating promoter recruitment, Co-IP showing physical association with c-Jun/c-Fos, loss-of-function with defined transcriptional and proliferation phenotype\",\n      \"pmids\": [\"19164581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of LKB1 in lung cancer cells is associated with underphosphorylation of endogenous CRTC1 and enhanced CRTC1 nuclear localization, leading to elevated expression of the CRTC1 target gene NR4A2/Nurr1. Inhibition of NR4A2 suppressed growth of LKB1-null tumors, placing CRTC1 downstream of the LKB1 tumor-suppressor pathway.\",\n      \"method\": \"Western blotting (phospho-CRTC1), immunofluorescence (nuclear localization), siRNA knockdown of NR4A2, colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation and localization measurements in cell lines plus functional NR4A2 knockdown, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20010869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Beta-amyloid suppresses CRTC1-dependent gene transcription in Alzheimer's disease model neurons by reducing calcium influx through L-type voltage-gated calcium channels, thereby disrupting PP2B/calcineurin-dependent dephosphorylation of CRTC1 at Ser151. Expression of constitutively active CRTC1 S151A or calcineurin mutants reversed transcriptional deficits. CRTC1-dependent memory genes (Bdnf, c-fos, Nr4a2) were selectively reduced coinciding with spatial memory deficits.\",\n      \"method\": \"Pharmacological manipulation (L-VGCC agonists/antagonists, NMDA/AMPA receptor blockers), phosphorylation assays, luciferase reporter, immunofluorescence, transgenic APP mouse model, behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphosite-specific rescue experiments (S151A mutant) plus pharmacological dissection in multiple assay systems and in vivo correlation\",\n      \"pmids\": [\"20631169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRTC1 functions in the suprachiasmatic nucleus (SCN) to regulate circadian clock entrainment. Light pulses cause CRTC1 to co-activate CREB, inducing Per1 and SIK1 expression. SIK1 then phosphorylates and deactivates CRTC1, providing negative feedback to suppress further light-induced clock shifts. Knockdown of Sik1 in the SCN increased behavioral phase shifts and rapid re-entrainment after experimental jet lag.\",\n      \"method\": \"SCN transcriptome analysis, in vivo Sik1 knockdown (lentiviral shRNA), behavioral phase-shift assays, immunohistochemistry, reporter assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined behavioral readout, combined with transcriptomic and biochemical characterization, published in high-tier journal\",\n      \"pmids\": [\"23993098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRTC1 (TORC1) shows rhythmic expression in the SCN and undergoes light-induced nuclear accumulation specifically in early and late subjective night. ChIP analysis confirmed that CRTC1 associates with CREB at the 5′ regulatory region of the Period1 gene; overexpression of CRTC1 markedly upregulates Period1 transcription. CRTC2 does not show photic regulation of subcellular localization in the SCN.\",\n      \"method\": \"Immunohistochemistry, chromatin immunoprecipitation, reporter gene assay, light-pulse paradigm in mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating CRTC1 occupancy at Per1 promoter combined with gain-of-function and direct localization experiment, single lab\",\n      \"pmids\": [\"23699513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRTC1 nuclear translocation in hippocampal neurons is regulated by convergence of constitutive kinase pathways and the activity-regulated phosphatase calcineurin. Nuclear CRTC1 binds CREB at IEG promoters in an activity-dependent manner. Forced nuclear expression of CRTC1 in hippocampal neurons activated CREB-dependent transcription and enhanced contextual fear memory. During contextual fear conditioning, endogenous CRTC1 nuclear recruitment occurred in the basolateral amygdala but not hippocampus; CRTC1 knockdown in the amygdala (but not hippocampus) attenuated fear memory.\",\n      \"method\": \"Region-specific viral CRTC1 knockdown, ChIP, immunofluorescence, contextual fear conditioning behavioral assay, reporter assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — region-specific loss-of-function with defined behavioral phenotype, ChIP showing promoter occupancy, and gain-of-function, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25277455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRTC1-MAML2 (C1/M2) oncoprotein gains a novel function by interacting with MYC proteins and activating MYC transcription targets involved in cell growth, metabolism, survival, and tumorigenesis. The C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, gene expression profiling, transformation assay in human MEC tumor cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical interaction plus functional transformation assay with defined MYC dependency, single lab\",\n      \"pmids\": [\"25071166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the hippocampus of APPSw,Ind Alzheimer's disease model mice, synaptic activity and spatial memory training induce CRTC1 dephosphorylation at Ser151 and nuclear translocation, and these events are impaired at early pathological and cognitive decline stages. AAV-mediated Crtc1 overexpression in the hippocampus reversed Aβ-induced spatial memory deficits by restoring a specific subset of Crtc1 target genes.\",\n      \"method\": \"AAV-mediated gene delivery, phosphorylation immunoassays, immunohistochemistry, microarray transcriptomics, Morris water maze behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue experiment (AAV-Crtc1) with defined behavioral and transcriptional readouts, phosphosite-specific biochemical measurements, combined with disease model\",\n      \"pmids\": [\"24760838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRTC1 is activated by PGE2 signaling in colon cancer cells through EP1 and EP2 receptor-mediated calcineurin and PKA activation, leading to CRTC1 dephosphorylation and nuclear translocation with enhanced CRTC1 transcriptional activity. CRTC1 loss of function reduced viability and cell division; stable CRTC1 overexpression increased xenograft tumor growth. CRTC1-activated genes including NR4A2, COX2, AREG and IL-6 depend on functional AP1 and CREB partners.\",\n      \"method\": \"Pharmacological receptor antagonists, calcineurin inhibitors, PKA modulators, phosphorylation assays, immunofluorescence, siRNA knockdown, stable overexpression, xenograft model, reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway dissected pharmacologically and confirmed by loss/gain-of-function with multiple in vitro and in vivo readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26300003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CRTC1 knockdown in hippocampal neurons impairs associative memory. Context-associative learning (but not single context or unconditioned stimuli alone) induces rapid dephosphorylation of CRTC1 at Ser151 and translocation from cytosol/dendrites to the nucleus, driving expression of c-fos and Nr4a1-3. This CRTC1 activation is disrupted in presenilin conditional double-knockout (neurodegeneration) mice. AAV-mediated CRTC1 gene therapy in the hippocampus ameliorated memory, transcriptional deficits and dendritic degeneration.\",\n      \"method\": \"One-trial contextual fear conditioning, phosphorylation assays, immunohistochemistry, ChIP, gene expression analysis, AAV gene therapy, presenilin cDKO mouse model\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function and rescue with defined behavioral and transcriptional phenotypes, phosphosite-specific biochemistry, ChIP showing promoter occupancy\",\n      \"pmids\": [\"27587263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRTC1 mediates preferential activity-dependent transcription at neuronal CRE/TATA-containing promoters. Neuronal activity and cAMP signals induce CRTC1 dephosphorylation, nuclear translocation, and activity-dependent binding to endogenous CREB; recruitment of CRTC1 to CRE/TATA promoters (c-fos, Dusp1, Nr4a1, Nr4a2, Ptgs2) is activity-dependent, whereas CREB itself is constitutively bound. Genes with CRE/TATA-less promoters are not induced.\",\n      \"method\": \"Chromatin immunoprecipitation, phosphorylation assays, immunofluorescence, luciferase reporter assays, neuronal depolarization/cAMP stimulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating activity-dependent CRTC1 recruitment to specific promoters combined with phosphorylation and reporter assays, single lab\",\n      \"pmids\": [\"29269871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRTC1-MAML2 fusion protein induces expression of LINC00473 lncRNA through CREB-mediated transcription, and this depends on the CRTC1-MAML2 ability to activate CREB. LINC00473 is required for MEC cell proliferation and survival in vitro and in vivo. LINC00473 binds the cAMP signaling component NONO, enhancing CRTC1-MAML2-driven CREB-mediated transcription.\",\n      \"method\": \"Lentiviral shRNA knockdown, xenograft tumor model, RNA immunoprecipitation (NONO binding), gene expression profiling, RNA ISH\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined proliferation/survival phenotype, RNA-protein interaction assay, single lab\",\n      \"pmids\": [\"29353885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIK1 phosphorylates CRTC1, preventing CRTC1 from enhancing CREB transcriptional activity for the expression of osteogenic genes such as Id1. BMP2 suppresses both SIK1 expression and SIK1 activity through PKA-dependent mechanisms to stimulate osteogenesis. SIK1 knockout mice display higher bone mass, osteoblast number, and bone formation rate.\",\n      \"method\": \"SIK1 kinase activity assay, SIK1 knockdown/knockout mice, osteoblast differentiation assays, bone mineralization assays, PKA inhibitor studies, phosphorylation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct kinase assay combined with in vivo knockout phenotype and defined molecular pathway (SIK1→CRTC1→CREB→Id1), multiple orthogonal methods\",\n      \"pmids\": [\"31672960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1-MAML2 is the major oncogenic driver of mucoepidermoid carcinoma (MEC). Doxycycline-induced knockdown of CRTC1-MAML2 blocked growth of established MEC xenografts. Conditional transgenic expression of CRTC1-MAML2 in mice caused 100% penetrant salivary gland tumor formation resembling human MEC histology. CRTC1-MAML2 activates AREG/EGFR signaling; combined CDK4/6 (Palbociclib) and EGFR (Erlotinib) inhibition produced enhanced antitumor responses in vitro and in vivo.\",\n      \"method\": \"Doxycycline-inducible shRNA knockdown, conditional transgenic mouse model, xenograft growth assays, molecular pathway analysis, combination drug treatment in vitro and in vivo\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional transgenic mouse model and in vivo knockdown both demonstrating oncogenic driver role, with defined molecular pathway, multiple orthogonal approaches\",\n      \"pmids\": [\"33830080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRTC1-MAML2 directs transcriptional activation of PGC-1α4 (a non-canonical splice variant), which regulates PPARγ-mediated IGF-1 expression. This autocrine IGF-1 circuit renders MEC cells selectively sensitive to IGF-1R inhibition and PPARγ inverse agonism.\",\n      \"method\": \"Gene expression profiling, small-molecule drug screens, reporter assays, IGF-1R inhibitor treatment, PPARγ inhibitor treatment, primary tumor molecular analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene expression and functional drug sensitivity data with mechanistic pathway (C1/M2→PGC-1α4→PPARγ→IGF-1), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33626346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMDAR activation in neurons induces dephosphorylation of CRTC1 at Ser151 and nuclear translocation, where CRTC1 competes with FXR for binding to CREB and drives autophagy gene expression required for late-phase long-term synaptic depression (L-LTD). Disrupting CRTC1-CREB interaction impaired transcription-dependent autophagy and prevented NMDAR-dependent L-LTD.\",\n      \"method\": \"Phosphorylation assays, immunofluorescence, co-immunoprecipitation (CRTC1-CREB, CRTC1-FXR competition), shRNA knockdown, electrophysiology (LTD recordings), autophagy assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing competition between CRTC1 and FXR for CREB binding, combined with loss-of-function electrophysiology readout, single lab\",\n      \"pmids\": [\"34289350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VDAC1 depletion increases free cytosolic Ca2+ in melanocytes, activating calcineurin through the Ca2+-calmodulin-calcineurin pathway, which dephosphorylates CRTC1 to facilitate its nuclear translocation and upregulate MITF transcription, increasing melanogenic gene expression (TYR, TYRP1, TYRP2).\",\n      \"method\": \"VDAC1 siRNA knockdown, Ca2+ imaging, calcineurin activity assay, CRTC1 phosphorylation assays, nuclear fractionation/immunofluorescence, reporter assays, VDAC1 knockout mice\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (VDAC1→Ca2+→calcineurin→CRTC1 dephosphorylation→nuclear translocation→MITF) established with multiple biochemical methods plus in vivo mouse confirmation, single lab\",\n      \"pmids\": [\"35649693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-184-3p directly targets CRTC1 mRNA; downregulation of miR-184-3p in human T2D pancreatic islets leads to upregulation of CRTC1, which protects β-cells from lipotoxicity- and inflammation-induced apoptosis. The protective effect of miR-184-3p inhibition is CRTC1-dependent, as CRTC1 silencing abrogates it. NKX6.1 directly controls miR-184 expression via binding sites in the MIR184 promoter.\",\n      \"method\": \"Chromatin immunoprecipitation (NKX6.1 binding to MIR184 promoter), mRNA and protein expression assays, CRTC1 siRNA silencing, luciferase miRNA target validation, apoptosis assays in human β-cells\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming NKX6.1 binding, validated miRNA-target interaction, loss-of-function showing CRTC1-dependency of protective phenotype, single lab\",\n      \"pmids\": [\"35906204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sustained expression of Mect1-Maml2 (CRTC1-MAML2) is required for MEC tumor cell growth. RNAi-mediated suppression of the fusion oncogene in parotid and pulmonary MEC cell lines with t(11;19) caused ≥90% colony growth inhibition, which could be partially rescued by co-expressing an RNAi-resistant Mect1-Maml2 mutant. Non-MEC tumor lines lacking the fusion were unaffected.\",\n      \"method\": \"shRNA knockdown, colony formation assay, rescue with RNAi-resistant mutant, in vivo nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selective knockdown with specific rescue experiment confirming on-target effect, in vivo xenograft validation, multiple cell line controls\",\n      \"pmids\": [\"16652146\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRTC1 is a CREB transcriptional coactivator that is held in the cytoplasm by phosphorylation (primarily at Ser151 by SIK-family kinases including SIK1 and SIK2) and translocates to the nucleus upon dephosphorylation by calcineurin downstream of Ca2+ and cAMP signals, where it binds CREB and preferentially activates CRE/TATA-containing gene promoters (including Per1, c-fos, Nr4a genes, and BDNF); SIK1 is itself a CREB/CRTC1 target gene that provides negative feedback by re-phosphorylating CRTC1; this pathway regulates circadian entrainment, memory consolidation, dendritic growth, osteoblast differentiation, and melanogenesis; chromosomal t(11;19) translocation fuses the CREB-binding domain of CRTC1 to MAML2, creating a constitutively active CREB coactivator that also engages c-Jun/c-Fos (AP-1), MYC, and PGC-1α/PPARγ/IGF-1 circuits to drive mucoepidermoid carcinoma initiation and maintenance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRTC1 is a calcium- and cAMP-responsive transcriptional coactivator for CREB that converts neuronal and hormonal signals into activity-dependent gene programs [#2, #13]. In the resting state it is held in the cytoplasm by phosphorylation at Ser151 by SIK-family kinases, and Ca2+ influx through L-type voltage-gated calcium channels triggers calcineurin (PP2B)-dependent dephosphorylation, nuclear translocation, and activity-dependent binding to constitutively promoter-bound CREB, where CRTC1 is selectively recruited to CRE/TATA-containing promoters to induce immediate-early and effector genes such as c-fos, Nr4a1-3, Dusp1, Ptgs2, Per1 and Bdnf [#2, #5, #13]. The coactivator is embedded in a self-limiting circuit: among its induced targets is SIK1, which re-phosphorylates CRTC1 to deplete it from the nucleus and terminate transcription [#2, #6]. Through this switch CRTC1 governs circadian clock entrainment in the suprachiasmatic nucleus via light-induced Per1 induction [#6, #7], drives dendritic growth and associative/fear memory consolidation in cortical, hippocampal and amygdalar neurons [#2, #8, #12], and supports SIK1-regulated osteoblast differentiation and the calcineurin-MITF melanogenic program [#15, #19]. CRTC1 signaling is corrupted in disease: amyloid-beta blunts L-VGCC/calcineurin-driven CRTC1 dephosphorylation to suppress memory genes in Alzheimer's models, and restoring CRTC1 reverses these transcriptional and behavioral deficits [#5, #10, #12]. The t(11;19) translocation fuses the N-terminal CREB-binding domain of CRTC1 to MAML2, generating a constitutively active coactivator that recruits p300/CBP to CREB and is the principal oncogenic driver of mucoepidermoid carcinoma, producing fully penetrant salivary gland tumors in mice [#0, #1, #16]; the fusion's CREB-binding domain is strictly required for transformation [#1, #21], and it additionally co-opts AP-1 (c-Jun/c-Fos), MYC, LINC00473/NONO, and PGC-1\\u03b1/PPAR\\u03b3-IGF-1 and AREG/EGFR circuits to sustain tumor growth [#3, #9, #14, #16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that the CRTC1-MAML2 fusion transforms cells by acting as a constitutive CREB coactivator, defining the oncogenic mechanism and CRTC1's intrinsic CREB-binding function.\",\n      \"evidence\": \"Co-IP, reporter assays and dominant-negative CREB rescue plus deletion mutagenesis in RK3E transformation assays\",\n      \"pmids\": [\"15961999\", \"16103063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the endogenous regulatory inputs controlling wild-type CRTC1\", \"Structural basis of CRTC1 CREB-binding domain interaction not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the fusion is continuously required for tumor maintenance, not merely initiation, validating it as a therapeutic dependency.\",\n      \"evidence\": \"shRNA knockdown with RNAi-resistant rescue in t(11;19) MEC lines and nude mouse xenografts\",\n      \"pmids\": [\"16652146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify downstream effector genes responsible for growth dependency\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the physiological activation switch: Ca2+/calcineurin-dependent dephosphorylation drives nuclear CRTC1 to support CREB-target genes and dendritic growth, with SIK1 forming a negative feedback loop.\",\n      \"evidence\": \"Live imaging, calcineurin/VGCC pharmacology, dominant-negative and siRNA in cortical neurons\",\n      \"pmids\": [\"19244510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the constitutive kinase(s) maintaining basal Ser151 phosphorylation not fully resolved\", \"Did not establish promoter selectivity rules\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended CRTC1's partner repertoire beyond CREB to AP-1, showing physical association with c-Jun/c-Fos drives both normal proliferation and fusion-driven transformation.\",\n      \"evidence\": \"ChIP, Co-IP, dominant-negative AP-1 and colony formation assays\",\n      \"pmids\": [\"19164581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CRTC1 recruitment to AP-1 promoters not defined\", \"Relative contribution of CREB vs AP-1 in transformation unquantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed CRTC1 downstream of the LKB1 tumor suppressor, where LKB1 loss underphosphorylates CRTC1 and elevates the NR4A2 target to support tumor growth.\",\n      \"evidence\": \"Phospho-CRTC1 Western blot, immunofluorescence and NR4A2 siRNA in LKB1-null lung cancer cells\",\n      \"pmids\": [\"20010869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether SIK-family kinases mediate the LKB1-CRTC1 link directly\", \"Single-lab, two-approach support\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked CRTC1 dysfunction to disease by showing amyloid-beta suppresses CRTC1 transcription via reduced L-VGCC Ca2+ influx and impaired Ser151 dephosphorylation, with S151A rescue.\",\n      \"evidence\": \"Phosphosite mutant rescue, L-VGCC pharmacology and behavior in APP transgenic mice\",\n      \"pmids\": [\"20631169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish causality between specific target genes and memory rescue\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated CRTC1's role in circadian entrainment, where light-driven CRTC1-CREB induction of Per1 and SIK1 creates feedback limiting phase shifts in the SCN.\",\n      \"evidence\": \"SCN transcriptomics, in vivo Sik1 knockdown, ChIP at Per1, and behavioral phase-shift/jet-lag assays\",\n      \"pmids\": [\"23993098\", \"23699513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CRTC1-specific (vs CRTC2) requirement for entrainment not tested by loss-of-function\", \"Per1 ChIP shows occupancy but not direct functional necessity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped region-specific behavioral roles, showing CRTC1 nuclear recruitment in the amygdala (not hippocampus) is required for fear memory, and AAV-CRTC1 rescues Alzheimer-model deficits.\",\n      \"evidence\": \"Region-specific viral knockdown, ChIP, AAV rescue and fear/water-maze behavior in mouse models\",\n      \"pmids\": [\"25277455\", \"24760838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of brain-region-specific CRTC1 activation not explained\", \"Which target-gene subset mediates rescue incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified MYC as a new fusion partner, with the CRTC1-MAML2-MYC interaction required for transformation, broadening the oncogenic transcriptional output.\",\n      \"evidence\": \"Co-IP, reporter and gene expression profiling with transformation assays in human MEC cells\",\n      \"pmids\": [\"25071166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of the MYC interaction not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established CRTC1 as an effector of PGE2/EP receptor signaling in colon cancer, where calcineurin/PKA-driven dephosphorylation activates proliferative and inflammatory target genes.\",\n      \"evidence\": \"Receptor antagonist/PKA/calcineurin pharmacology, loss/gain-of-function and xenografts\",\n      \"pmids\": [\"26300003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative requirement of AP-1 vs CREB partners for each target gene not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the learning-specificity of CRTC1, showing context-association (not stimuli alone) triggers Ser151 dephosphorylation and nuclear translocation driving IEGs, with gene therapy rescuing degeneration.\",\n      \"evidence\": \"One-trial fear conditioning, phospho-assays, ChIP, AAV gene therapy in presenilin cDKO mice\",\n      \"pmids\": [\"27587263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal distinguishing association from single stimuli unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the promoter-selectivity rule: activity-dependent CRTC1 recruitment occurs specifically at CRE/TATA promoters while CREB is constitutively bound, explaining gene-selective induction.\",\n      \"evidence\": \"ChIP across CRE/TATA vs CRE/TATA-less promoters with phospho and reporter assays in stimulated neurons\",\n      \"pmids\": [\"29269871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TATA element confers CRTC1 dependence unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified LINC00473/NONO as a downstream effector and feed-forward amplifier of fusion-driven CREB transcription required for MEC survival.\",\n      \"evidence\": \"shRNA knockdown, xenografts, RNA-IP for NONO and expression profiling\",\n      \"pmids\": [\"29353885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of LINC00473-NONO enhancement of CREB transcription not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed direct SIK1-CRTC1 regulation in a non-neural context, where SIK1 phosphorylation of CRTC1 restrains CREB-driven osteogenic genes like Id1.\",\n      \"evidence\": \"SIK1 kinase assay, SIK1 knockout mice, osteoblast differentiation and PKA inhibitor studies\",\n      \"pmids\": [\"31672960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser151 is the relevant SIK1 site in osteoblasts not specified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated CRTC1-MAML2 as the major MEC driver and revealed actionable AREG/EGFR, PGC-1\\u03b14/PPAR\\u03b3-IGF-1 circuits enabling combination therapy.\",\n      \"evidence\": \"Conditional transgenic mouse, inducible knockdown, drug screens and combination treatment in vitro/in vivo\",\n      \"pmids\": [\"33830080\", \"33626346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PGC-1\\u03b14/IGF-1 arm is Medium-confidence single-lab\", \"Direct vs indirect target relationships not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a transcription-coupled autophagy role, where NMDAR-driven CRTC1 competes with FXR for CREB to induce autophagy genes needed for late-phase LTD.\",\n      \"evidence\": \"Co-IP competition, phospho-assays, shRNA and LTD electrophysiology\",\n      \"pmids\": [\"34289350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CRTC1/FXR competition not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the Ca2+/calcineurin-CRTC1 axis to melanogenesis (VDAC1->Ca2+->MITF) and to beta-cell survival via miR-184-3p targeting of CRTC1 mRNA.\",\n      \"evidence\": \"VDAC1 knockdown/KO, Ca2+ imaging, calcineurin assays, miRNA target validation and apoptosis assays\",\n      \"pmids\": [\"35649693\", \"35906204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MITF promoter occupancy by CRTC1 not shown\", \"miR-184-3p/CRTC1 protective targets in beta-cells not enumerated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CRTC1 promoter selectivity, the full set of kinases setting basal phosphorylation, and how cell-type context dictates which target programs CRTC1 activates remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CRTC1-CREB-CRE/TATA assembly\", \"Determinants of tissue-specific target selection unknown\", \"Mechanism linking distinct upstream signals to common CRTC1 dephosphorylation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 8, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [14, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 7, 8, 10, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 11, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 16, 5]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\"CRTC1-CREB coactivator complex\"],\n    \"partners\": [\"CREB\", \"MAML2\", \"CREBBP/EP300\", \"JUN\", \"FOS\", \"MYC\", \"SIK1\", \"NONO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}