Affinage

CRTC3

CREB-regulated transcription coactivator 3 · UniProt Q6UUV7

Length
619 aa
Mass
67.0 kDa
Annotated
2026-04-28
34 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRTC3 is a transcriptional coactivator of CREB that integrates hormonal, metabolic, and stress signals to control diverse gene programs in energy homeostasis, immunity, pigmentation, and hematopoiesis. In its basal state, SIK-mediated phosphorylation promotes 14-3-3 binding and cytoplasmic sequestration of CRTC3; upstream signals—including cAMP/PKA, PGE2, and catecholamines—inhibit SIKs or activate B55-containing PP2A phosphatases (recruited via ERK/CDK-phosphorylated S391), causing CRTC3 dephosphorylation and nuclear translocation (PMID:23033494, PMID:30611118). Once nuclear, CRTC3 coactivates CREB to drive context-specific targets: IL-10 in macrophages, Rgs2 in adipocytes (attenuating β-adrenergic/adenylyl cyclase signaling and promoting obesity), UCP1 in brown adipose tissue (via C/EBPβ recruitment), MITF in melanocytes, SOCS3 in bone marrow stromal cells (restraining JAK/STAT-driven granulopoiesis), and amphiregulin in astrocytes (PMID:23241891, PMID:21164481, PMID:27461402, PMID:34815795, PMID:29078378, PMID:37730843). CRTC3 activity is further modulated by PRMT1-mediated arginine methylation at R534, which redirects it to cooperate with FOXO3a in BAX-dependent apoptosis in skeletal muscle (PMID:40192801).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2010 High

    The first in vivo function of CRTC3 was established: it promotes obesity by activating Rgs2 transcription in adipocytes, which dampens β-adrenergic/adenylyl cyclase signaling and reduces energy expenditure, with a common human variant conferring increased transcriptional activity and adiposity.

    Evidence Crtc3 knockout mice, adenoviral overexpression, Rgs2 and adenylyl cyclase assays, human SNP association

    PMID:21164481

    Open questions at the time
    • Mechanism by which the human CRTC3 variant increases transcriptional activity is not defined
    • Whether Rgs2 is the sole effector of CRTC3 in adipocytes is unclear
  2. 2011 Medium

    CRTC3 was shown to have isoform-specific functions distinct from CRTC2, selectively mediating mitochondrial stress-induced PGC-1α expression and mitochondrial biogenesis in hepatocytes.

    Evidence siRNA knockdown of CRTC2 vs CRTC3 in HepG2 cells and primary hepatocytes under rotenone treatment

    PMID:21536665

    Open questions at the time
    • No in vivo validation of hepatic CRTC3-specific mitochondrial function
    • Mechanism distinguishing CRTC3 from CRTC2 specificity at the PGC-1α promoter is unknown
  3. 2012 High

    The core regulatory mechanism of CRTC3 was defined: SIK phosphorylation drives 14-3-3-dependent cytoplasmic retention, while SIK inhibition (by PKA downstream of PGE2 or pharmacological agents) releases CRTC3 for nuclear translocation and CREB coactivation, establishing CRTC3 as a key mediator of IL-10 transcription in macrophages independently of CREB Ser133 phosphorylation.

    Evidence Drug-resistant SIK2 mutant rescue, endogenous CREB S133A knock-in, subcellular fractionation, IL-10 promoter assays in macrophages

    PMID:23033494 PMID:23241891

    Open questions at the time
    • Relative contributions of individual SIK family members to CRTC3 regulation in different tissues not delineated
    • Whether CRTC3 regulation of IL-10 is relevant beyond in vitro macrophage systems was not established at this time
  4. 2016 High

    The LKB1–SIK–CRTC3 axis was extended to thermogenesis: LKB1 deletion in brown adipocytes caused CRTC3 nuclear translocation, where it recruited C/EBPβ to activate UCP1 transcription, establishing CRTC3 as a direct coactivator at the UCP1 promoter.

    Evidence Adipocyte-specific Lkb1 knockout mice, co-IP of CRTC3 with C/EBPβ, UCP1 promoter assays, metabolic phenotyping

    PMID:27461402

    Open questions at the time
    • Whether CRTC3 acts through CREB or exclusively through C/EBPβ at the UCP1 promoter was not resolved
    • Contribution of CRTC3 vs CRTC2 to thermogenic programming not distinguished
  5. 2017 High

    Combined CRTC2/CRTC3 loss revealed an essential and partially redundant role in hematopoietic regulation: the CREB/CRTC complex maintains SOCS3 expression, restraining JAK/STAT3 signaling and preventing pathological neutrophilia.

    Evidence CRTC2/3 double KO mice (embryonic lethal), mesenchymal-specific conditional KO, adoptive BM transfer, JAK inhibitor and anti-G-CSF rescue

    PMID:29078378

    Open questions at the time
    • Individual contribution of CRTC3 versus CRTC2 to SOCS3 regulation not separated
    • Whether CRTC3 regulates other SOCS family members is unknown
  6. 2018 High

    Multiple tissue-specific and biochemical advances converged: CRTC3 was shown to antagonize BAT differentiation via miR-206/VEGFA/neurotrophin-dependent sympathetic innervation, its phosphatase specificity for B55 PP2A (not calcineurin) was biochemically defined with ERK/CDK phosphorylation of S391 as the trigger, and its role downstream of PTH signaling in osteoblasts for Rankl expression was demonstrated.

    Evidence BAT-specific CRTC3 KO and constitutively active OE mice with miR-206 rescue; Co-IP/MS of CRTC3-PP2A with S391 mutagenesis; SIK/CRTC3 knockdown in osteoblasts with Rankl assays

    PMID:29784793 PMID:30377251 PMID:30611118

    Open questions at the time
    • Structural basis of CRTC3 selectivity for PP2A B55 over calcineurin is unresolved
    • Whether S391 phosphorylation integrates signals beyond ERK/CDK is unknown
    • Relative importance of CRTC3 vs other CRTCs in PTH-driven bone remodeling not defined
  7. 2021 Medium

    CRTC3 was established as a quantitative regulator of melanogenesis by directly coactivating MITF transcription, and this pathway was co-opted in melanoma where SIK2 inhibition by dasatinib activates CRTC3→MITF→Bcl-2 as a drug resistance mechanism; separately, SIK inhibition-induced nuclear CRTC3 and IL-10 production was validated in vivo in a colitis model.

    Evidence CRTC3 KO mice with coat color/melanin phenotype, shRNA in melanocytes, MITF promoter assays; dasatinib-treated c-Kit melanoma with Bcl-2 KO rescue; SIK OE in macrophages and TNBS colitis mice

    PMID:33741716 PMID:33988718 PMID:34815795

    Open questions at the time
    • Whether CRTC3 regulation of MITF is relevant in human melanogenesis disorders is untested
    • In vivo confirmation of CRTC3-dependent drug resistance in melanoma is lacking
  8. 2023 Medium

    CRTC3 function was extended to brain circuitry and cancer metabolism: astrocyte-specific CRTC3 drives amphiregulin expression to maintain prefrontal-parietal connectivity and social dominance, while in hepatocellular carcinoma CRTC3 loss rewires lipid metabolism toward PUFA accumulation and ferroptosis sensitivity.

    Evidence Astrocyte-specific CRTC3 KO with amphiregulin rescue and functional connectivity imaging; CRISPR screen in HCC lines with lipidomics and in vivo tumor models

    PMID:37666810 PMID:37730843

    Open questions at the time
    • Direct CRTC3 transcriptional targets controlling lipid remodeling in HCC are not identified
    • Human relevance of astrocytic CRTC3 in social behavior is unknown
    • Mechanism linking CRTC3 loss to PUFA accumulation not defined
  9. 2024 Medium

    A non-transcriptional function of CRTC3 was uncovered: direct interaction with SARS-CoV-2 NSP12 attenuates RNA-dependent RNA polymerase activity and restricts viral replication, with CREB antagonizing this restriction.

    Evidence Co-IP of CRTC3 with NSP12, RdRp activity assays, CRTC3 OE/KO viral replication assays

    PMID:39736320

    Open questions at the time
    • Whether CRTC3 inhibits RdRp via direct catalytic interference or allosteric mechanism is unknown
    • Physiological relevance in human SARS-CoV-2 infection not established
    • How CREB antagonizes the antiviral function of CRTC3 is mechanistically undefined
  10. 2025 Medium

    A post-translational activation mode was defined: PRMT1-mediated methylation at R534 in the CRTC3 transactivation domain redirects CRTC3 to cooperate with FOXO3a (rather than CREB) to transactivate BAX and promote apoptosis, linking CRTC3 to muscle atrophy.

    Evidence IP-MS identification of R534 methylation, Co-IP of CRTC3-FOXO3a, R534 mutagenesis, PRMT1 inhibition, BAX inhibitor rescue in vivo

    PMID:40192801

    Open questions at the time
    • Whether R534 methylation occurs in tissues beyond muscle is unknown
    • Structural basis for how methylation switches CRTC3 partner preference from CREB to FOXO3a is unresolved
    • Independent replication is needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CRTC3's selective use of PP2A B55 over calcineurin, whether R534 methylation represents a general partner-switching mechanism across tissues, and how CRTC3 achieves target gene specificity when coactivating different transcription factors (CREB, C/EBPβ, MITF, FOXO3a) in distinct cell types.
  • No high-resolution structural data for CRTC3 or its complexes exist
  • Genome-wide identification of direct CRTC3 target genes across tissues has not been performed
  • Relative contributions of CRTC3 versus CRTC1/CRTC2 in most tissues are poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CEBPBCREB1FOXO3MITFPPP2CAPRMT1SIK2YWHAZ

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Salt-inducible kinases (SIKs) phosphorylate CRTC3, causing it to associate with 14-3-3 proteins and be sequestered in the cytoplasm; SIK inhibition leads to CRTC3 dephosphorylation, dissociation from 14-3-3 proteins, nuclear translocation, and coactivation of CREB-driven IL-10 transcription in macrophages, promoting a regulatory macrophage phenotype. Pharmacological SIK inhibition, drug-resistant SIK2 mutant rescue experiment, subcellular fractionation/localization, gene transcription assays Proceedings of the National Academy of Sciences of the United States of America High 23033494
2012 PGE2 activates PKA, which phosphorylates SIK2 at Ser343, inhibiting SIK2's ability to phosphorylate CRTC3; this allows CRTC3 to translocate to the nucleus and coactivate CREB-driven IL-10 transcription independently of CREB Ser133 phosphorylation. Endogenous CREB Ser133Ala knock-in mutation, pharmacological and genetic SIK inhibition, subcellular localization assays, IL-10 promoter transcription assays Journal of immunology (Baltimore, Md. : 1950) High 23241891
2010 CRTC3 is activated by catecholamine/cAMP signals in adipocytes and promotes obesity by upregulating Rgs2 expression, which inhibits adenylyl cyclase activity and attenuates β-adrenergic receptor signaling; a common human CRTC3 variant with increased transcriptional activity is associated with adiposity. Crtc3 knockout mice, adenoviral overexpression, Rgs2 expression assays, adenylyl cyclase activity measurement, human cohort SNP analysis Nature High 21164481
2018 CRTC3 selectively interacts with B55 PP2A holoenzymes (not calcineurin, unlike CRTC1/2) via a conserved PP2A-binding region (amino acids 380–401); phosphorylation of CRTC3 at S391 by ERKs and CDKs promotes CRTC3-PP2A complex formation, facilitating dephosphorylation of 14-3-3 binding sites and nuclear translocation of CRTC3 in response to mitogenic signals. Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis of PP2A-binding region and S391, kinase inhibitor studies iScience High 30611118
2016 Lkb1 controls intracellular localization of CRTC3 in brown adipocytes; deletion of Lkb1 causes cytoplasm-to-nucleus translocation of CRTC3, where it recruits C/EBPβ to enhance Ucp1 transcription, increasing thermogenesis and energy expenditure. Adipocyte-specific Lkb1 knockout mice, subcellular fractionation, co-immunoprecipitation of CRTC3 with C/EBPβ, Ucp1 promoter assays, metabolic phenotyping Nature communications High 27461402
2018 CRTC3 in brown adipose tissue acts as part of an inhibitory feedback pathway that antagonizes PRDM16-dependent BAT differentiation by upregulating miR-206, a microRNA that promotes myogenic differentiation and reduces VEGFA and neurotrophin expression, thereby decreasing sympathetic innervation and catecholamine signaling in BAT. BAT-specific CRTC3 knockout mice, adipose-specific constitutively active CRTC3 overexpression mice, miR-206 reexpression rescue experiment, sympathetic nerve activity measurement Proceedings of the National Academy of Sciences of the United States of America High 29784793
2011 CRTC3, but not CRTC2, is selectively required for mitochondrial stress-induced (rotenone/complex I inhibition) PGC-1α induction and downstream mitochondrial biogenesis in liver cells. siRNA knockdown of CRTC2 and CRTC3 in HepG2 cells and primary mouse hepatocytes, PGC-1α expression assays, mitochondrial biogenesis readouts The Journal of biological chemistry Medium 21536665
2018 In osteoblasts, PTH(1-34) regulates Rankl expression through a pathway involving PKA-mediated inhibition of SIK2 and SIK3, which controls CRTC3 nuclear localization; PP1/PP2A phosphatases also play a major role in PTH-induced Rankl expression and CRTC3 localization. SIK2/SIK3 and CRTC3 knockdown in primary calvarial osteoblasts, nuclear localization assays, PP1/PP2A inhibition, Rankl expression assays in vitro and in vivo The Journal of biological chemistry Medium 30377251
2017 Disruption of both CRTC2 and CRTC3 causes embryonic lethality in mice; in bone marrow stromal cells, CRTC2/3 depletion decreases SOCS3 expression, leading to increased STAT3 phosphorylation and CEBPβ induction, which drives G-CSF production and neutrophilia/splenomegaly. CRTC2/CRTC3 double knockout mice, mesenchymal cell-specific Prx1-Cre conditional knockout, adoptive BM transfer, JAK inhibitor treatment, anti-G-CSF neutralizing antiserum Proceedings of the National Academy of Sciences of the United States of America High 29078378
2021 CRTC3 quantitatively regulates melanogenesis by directly targeting MITF transcription; CRTC3-null mice show paler coat color and reduced melanin, and CRTC3-deficient melanocytes have reduced melanogenesis-related gene expression without loss of melanocyte number. CRTC3 knockout mice, KRT14-SCF transgenic crosses, shRNA knockdown in primary melanocytes, promoter assays, melanin/tyrosinase assays, subcellular localization studies Theranostics Medium 34815795
2021 Dasatinib inhibits SIK2, leading to reduced CRTC3 phosphorylation and nuclear accumulation of CRTC3, which activates CREB-driven MITF transcription; MITF then transcriptionally activates Bcl-2, conferring resistance to dasatinib in c-Kit-altered melanoma cells. CRTC3 phosphorylation assays, MITF/Bcl-2 expression analysis, MITF overexpression, Bcl-2 selective inhibitor (ABT-199), Bcl-2 knockout, cell viability assays Molecular cancer research : MCR Medium 33741716
2023 CRTC3 in astrocytes directly regulates transcription of amphiregulin (in complex with CREB); astrocyte-specific CRTC3 deficiency reduces prefrontal-parietal cortex functional connectivity and lowers social rank, effects reversed by astrocyte-specific amphiregulin induction dependent on its EGF domain. Systemic and astrocyte-specific CRTC3 knockout mice, functional connectivity imaging, astrocyte-specific amphiregulin rescue, promoter/CRTC3-CREB binding assays, tube test for social hierarchy Molecular psychiatry Medium 37730843
2024 CRTC3 interacts with NSP12 (the catalytic subunit of SARS-CoV-2 RdRp), attenuates RdRp activity, and restricts SARS-CoV-2 genome replication and progeny virus production; CREB antagonizes this restrictive function of CRTC3. Co-immunoprecipitation of CRTC3 with NSP12, RdRp activity assays, SARS-CoV-2 replication assays, CRTC3 overexpression/knockout, CREB co-expression Virologica Sinica Medium 39736320
2025 PRMT1 methylates CRTC3 at arginine R534 within its transactivation domain; this activated CRTC3 cooperates with FOXO3a to transactivate the BAX gene, promoting apoptosis and muscle atrophy in the context of dietary advanced glycation end-products. Immunoprecipitation, mass spectrometry, co-immunoprecipitation, site-specific mutagenesis at R534, PRMT1 inhibition, BAX inhibitor in vivo, proteomic analysis of muscle tissue Cellular and molecular life sciences : CMLS Medium 40192801
2023 CRTC3 knockout alters tumor cell lipid patterns, increasing polyunsaturated fatty acid (PUFA) abundance and lipid peroxidation susceptibility, enhancing ferroptosis in hepatocellular carcinoma cells; IFN-γ synergizes with CRTC3 knockout by inhibiting system xc- (SLC7A11), disrupting a compensatory mechanism upregulated upon CRTC3 loss. CRISPR/Cas9 genome-wide knockout screen, CRTC3 KO in HCC cell lines, lipidomic analysis, ferroptosis inducers (RSL3, erastin, sorafenib), in vitro and in vivo tumor models Cell death discovery Medium 37666810
2021 SIK inhibitor HG-9-91-01 increases nuclear CRTC3 levels in colonic macrophages and promotes IL-10 production; overexpression of SIKs reduces nuclear CRTC3 and abrogates the anti-inflammatory effect both in vitro and in vivo. Lentiviral SIK overexpression in ANA-1 macrophages and in TNBS colitis mice, nuclear CRTC3 localization assays, IL-10 measurement, colitis mouse models Inflammatory bowel diseases Medium 33988718
2018 Cold exposure induces nuclear translocation of CRTC3 in brown adipose tissue; this is associated with decreased Lkb1 expression; PKA activator forskolin also induces CRTC3 nuclear translocation in brown adipocytes, linked to UCP1 upregulation. Cold exposure mouse model, subcellular fractionation/immunofluorescence of CRTC3 localization in BAT, forskolin treatment of brown adipocytes, Lkb1 expression assays Journal of cellular biochemistry Low 30506739

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proceedings of the National Academy of Sciences of the United States of America 213 23033494
2012 PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. Journal of immunology (Baltimore, Md. : 1950) 195 23241891
2009 Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 133 19749740
2010 CRTC3 links catecholamine signalling to energy balance. Nature 128 21164481
2016 Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3. Nature communications 76 27461402
2018 Parathyroid hormone(1-34) and its analogs differentially modulate osteoblastic Rankl expression via PKA/SIK2/SIK3 and PP1/PP2A-CRTC3 signaling. The Journal of biological chemistry 57 30377251
2011 Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. The Journal of biological chemistry 56 21536665
2013 CRTC1-MAML2 and CRTC3-MAML2 fusions were not detected in metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands. The American journal of surgical pathology 37 24121173
2017 A novel fusion gene CRTC3-MAML2 in hidradenoma: histopathological significance. Human pathology 33 29079171
2016 Cutaneous hidradenoma: a study of 21 neoplasms revealing neither correlation between the cellular composition and CRTC1-MAML2 fusions nor presence of CRTC3-MAML2 fusions. Annals of diagnostic pathology 27 27402217
2018 cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis. Proceedings of the National Academy of Sciences of the United States of America 26 29784793
2021 CRTC3 Regulates the Lipid Metabolism and Adipogenic Differentiation of Porcine Intramuscular and Subcutaneous Adipocytes by Activating the Calcium Pathway. Journal of agricultural and food chemistry 20 34142819
2018 Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment. iScience 18 30611118
2017 CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America 17 29078378
2021 CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders. Theranostics 15 34815795
2023 In vitro CRISPR screening uncovers CRTC3 as a regulator of IFN-γ-induced ferroptosis of hepatocellular carcinoma. Cell death discovery 14 37666810
2020 Breed difference and regulatory role of CRTC3 in porcine intramuscular adipocyte. Animal genetics 14 32400010
2018 Cold exposure induces nuclear translocation of CRTC3 in brown adipose tissue. Journal of cellular biochemistry 14 30506739
2013 CRTC3 polymorphisms were associated with the plasma level of total cholesterol and the risks of overweight and hypertriglyceridemia in a Chinese Han population. Molecular biology reports 14 24264430
2018 Genetic variants and haplotype combination in the bovine CRTC3 affected conformation traits in two Chinese native cattle breeds (Bos Taurus). Genomics 13 30529539
2021 Comprehensive evaluation of the metabolic effects of porcine CRTC3 overexpression on subcutaneous adipocytes with metabolomic and transcriptomic analyses. Journal of animal science and biotechnology 12 33653408
2021 HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway. Inflammatory bowel diseases 12 33988718
2017 Regulation role of CRTC3 in skeletal muscle and adipose tissue. Journal of cellular physiology 12 28322447
2016 Soluble CRTC3: A Newly Identified Protein Released by Adipose Tissue That Is Associated with Childhood Obesity. Clinical chemistry 11 26797688
2017 Genomic characterization of the porcine CRTC3 and the effects of a non-synonymous mutation p.V515F on lean meat production and belly fat. Meat science 9 29220752
2021 Dasatinib Stimulates Its Own Mechanism of Resistance by Activating a CRTC3/MITF/Bcl-2 Pathway in Melanoma with Mutant or Amplified c-Kit. Molecular cancer research : MCR 7 33741716
2023 Amphiregulin normalizes altered circuit connectivity for social dominance of the CRTC3 knockout mouse. Molecular psychiatry 6 37730843
2024 CRTC3 restricts SARS-CoV-2 replication and is antagonized by CREB. Virologica Sinica 4 39736320
2024 Breast mucoepidermoid carcinoma with a rare CRTC3-MAML2 fusion. International cancer conference journal 3 39398906
2018 Rapid Communication: Porcine CRTC3 gene clone, expression pattern, and its regulatory role in intestinal epithelial cells. Journal of animal science 3 29796654
2025 Dietary advanced glycation end-products exacerbate sarcopenia onset by activating apoptosis through PRMT1-mediated CRTC3 arginine methylation. Cellular and molecular life sciences : CMLS 2 40192801
2024 Semaxanib, a VEGF inhibitor, suppresses melanogenesis by modulating CRTC3 independently of VEGF signaling. Journal of dermatological science 2 39127591
2021 Morphological and biological properties of silica nanoparticles for CRTC3-siRNA delivery and downregulation of the RGS2 expression in preadipocytes. Journal of biomaterials applications 2 33947275
2025 Penile mucoepidermoid carcinoma lacking CRTC1/CRTC3-MAML2 fusion: a case report and review of the literature. International cancer conference journal 0 41589253