Affinage

CRTC2

CREB-regulated transcription coactivator 2 · UniProt Q53ET0

Length
693 aa
Mass
73.3 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRTC2 (TORC2) is a phosphorylation-gated transcriptional coactivator that couples nutrient and hormonal signals to CREB-dependent gene programs, most prominently the hepatic gluconeogenic response to fasting (PMID:16148943, PMID:20133702). Under fed/resting conditions it is held in the cytoplasm through phosphorylation-dependent 14-3-3 binding, with SIK2 and the phosphatase calcineurin both associating with CRTC2 to set its phosphorylation state at the 14-3-3 sites Ser171 and Ser275; fasting-induced cAMP inhibits SIK2 while calcium-activated calcineurin dephosphorylates these sites, driving nuclear entry and CREB coactivation (PMID:15454081, PMID:18626018). Insulin reverses this by AKT2-dependent activation of SIK2, which rephosphorylates Ser171 and triggers COP1-mediated ubiquitination at Lys628 and 26S proteasomal degradation of CRTC2 (PMID:17805301). In the nucleus, CRTC2's N-terminal CREB-binding domain folds into a single 28-residue helix that contacts the CREB bZip and CRE-containing DNA, assembling a 2:2 CRTC2–CREB complex on DNA that stabilizes CREB occupancy and confers DNA-shape selectivity (PMID:23213254, PMID:29733854). Beyond gluconeogenesis, CRTC2 governs hepatic lipogenesis by competing with the COPII subunit Sec23A for Sec31A to restrain SREBP1 ER-to-Golgi processing, an inhibition relieved by mTOR phosphorylation during feeding (PMID:26147081), and acts as a broad CREB-axis coactivator across additional programs by partnering with CBP/p300 to deposit H3K27ac at inflammatory loci downstream of LKB1–SIK signaling (PMID:37172591) and by coactivating the glucocorticoid receptor (PMID:26652733). Its activity is constitutively elevated in LKB1-deficient cancers, where loss of SIK-mediated inhibitory phosphorylation drives CREB target genes such as ID1 (PMID:31355336).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Established the core regulatory logic of CRTC2: how opposing kinase and phosphatase inputs gate its cytoplasmic sequestration versus nuclear CREB coactivation.

    Evidence Co-IP, kinase assays, calcineurin inhibition and SIK2 knockdown with subcellular imaging

    PMID:15454081

    Open questions at the time
    • Did not map the specific phospho-sites bound by 14-3-3
    • Physiological signal triggering calcineurin/SIK2 not yet placed in a whole-animal context
  2. 2005 High

    Placed CRTC2 in vivo as the fasting/glucagon-responsive driver of the hepatic gluconeogenic transcriptional program and identified AMPK as an opposing input.

    Evidence Subcellular fractionation, reporter assays and adenoviral gain/loss-of-function in mice with pharmacological AMPK activation

    PMID:16148943

    Open questions at the time
    • Did not resolve how multiple kinases converge on the same 14-3-3 sites
    • Mechanism of insulin-mediated shut-off unresolved
  3. 2007 High

    Defined the insulin-driven OFF switch — how CRTC2 is targeted for degradation rather than merely re-exported.

    Evidence In vivo mouse studies, site-directed mutagenesis (Ser171, Ser358, Lys628), ubiquitination and proteasome-inhibitor assays

    PMID:17805301

    Open questions at the time
    • Did not address regulation of COP1 activity itself
    • Relative contribution of degradation versus cytoplasmic retention to CRTC2 silencing not quantified
  4. 2008 High

    Extended the phospho-code beyond Ser171 by identifying Ser275 as a second glucose-regulated 14-3-3 site essential for CREB activation in beta cells.

    Evidence Cell-based kinase screen of 180 kinases, Ser275 mutagenesis, calcineurin inhibition and islet studies

    PMID:18626018

    Open questions at the time
    • Hierarchy/interplay between Ser171 and Ser275 phosphorylation not fully resolved
    • Role of MARK2 in vivo not established
  5. 2009 High

    Broadened CRTC2 from a metabolic to a stress-integrating coactivator and showed ER stress can redirect it away from gluconeogenic genes via ATF6α.

    Evidence Reciprocal Co-IP, ChIP and adenoviral knockdown/overexpression in mouse liver

    PMID:19543265

    Open questions at the time
    • Structural basis of ATF6α disruption of CREB-CRTC2 not defined
    • Whether ER-stress and fasting inputs are integrated at the same molecule simultaneously unclear
  6. 2010 High

    Confirmed by loss-of-function genetics that the N-terminal CREB-binding domain mediates promoter occupancy and is required for the fasting glucose response.

    Evidence CRTC2 knockout mice with ChIP, reporter assays and glucose tolerance tests

    PMID:20133702

    Open questions at the time
    • Atomic detail of the CBD-CREB interface not yet resolved
    • Did not address CREB-independent CRTC2 functions
  7. 2012 High

    Resolved the molecular architecture of coactivation, showing the CBD is an isolated helix forming a defined 2:2:1 CRTC-CREB-CRE assembly.

    Evidence NMR/structural analysis, mutagenesis and binding-affinity measurements with reporter validation

    PMID:23213254

    Open questions at the time
    • Did not capture direct CRTC2-DNA contacts
    • How phosphorylation alters the helix or its accessibility not addressed
  8. 2018 High

    Crystallography revealed that CRTC2 contacts DNA directly and reads intrinsic DNA shape, explaining promoter selectivity and CREB stabilization on the CRE.

    Evidence X-ray crystallography of the CBD-bZip-CRE complex with structure-guided mutagenesis and reporter assays

    PMID:29733854

    Open questions at the time
    • Structure of full-length phospho-regulated CRTC2 not determined
    • How DNA-shape selectivity is modulated in vivo by chromatin unknown
  9. 2015 High

    Identified a transcription-independent CRTC2 function — control of hepatic lipogenesis by competing for COPII subunits to gate SREBP1 trafficking.

    Evidence Reciprocal/competition Co-IP, SREBP1 processing assays and adenoviral mTOR-defective CRTC2 mutant in obese mice

    PMID:26147081

    Open questions at the time
    • Stoichiometry of CRTC2 versus Sec23A at COPII coats not quantified
    • Whether nuclear and ER pools of CRTC2 are distinct populations unresolved
  10. 2023 High

    Connected CRTC2 to chromatin modification, showing it recruits CBP/p300 to deposit H3K27ac at inflammatory loci downstream of LKB1-SIK signaling.

    Evidence ChIP-seq/H3K27ac profiling, LKB1 knockout cells, CRTC2 manipulation and Co-IP with CBP/p300

    PMID:37172591

    Open questions at the time
    • Whether CRTC2 itself directs HAT specificity or is a passive scaffold unclear
    • Generality of CRTC2-driven H3K27ac beyond inflammatory genes not tested
  11. 2015 Medium

    Expanded the transcription-factor partner repertoire beyond CREB by showing CRTC2 coactivates the glucocorticoid receptor for gluconeogenic genes.

    Evidence Co-IP with domain mapping (aa 561–693 to GR LBD), ChIP, reporter assays and knockout mice

    PMID:26652733

    Open questions at the time
    • Single lab; reciprocal structural validation of the GR interface absent
    • Whether GR and CREB coactivation occur on shared or distinct promoters not resolved
  12. 2019 Medium

    Demonstrated a pathological gain-of-function: constitutive CRTC2 activation in LKB1-mutant cancer drives tumor growth through CREB target genes.

    Evidence LKB1-mutant NSCLC analysis, shRNA knockdown, ChIP and tumor growth assays

    PMID:31355336

    Open questions at the time
    • Single-lab epistasis; direct dependence on SIK reactivation not fully separated from other LKB1 effectors
    • Breadth of CRTC2-dependent oncogenic targets beyond ID1 not defined
  13. 2021 Medium

    Identified Sam68 as a stabilizing partner that limits CRTC2 ubiquitination, adding a post-translational tuning node controlling gluconeogenesis.

    Evidence Co-IP with deletion mapping, ubiquitination assays and global/hepatic Sam68 KO mice

    PMID:34099657

    Open questions at the time
    • Single lab; how Sam68 competes with COP1 mechanistically not defined
    • Whether Sam68 acts on cytoplasmic or nuclear CRTC2 unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many context-specific CRTC2 functions (lipogenesis, chromatin marking, GR/ATF6α/viral coactivation, neuronal and reproductive programs) are partitioned within a single cell — and what determines partner and promoter selectivity beyond phosphorylation state — remains unresolved.
  • No unified model linking the cytoplasmic COPII-gating role to nuclear coactivation
  • Determinants of transcription-factor partner choice (CREB vs GR vs ATF6α) not established
  • Structure of phospho-regulated full-length CRTC2 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ATF6COP1CREB1CREBBP/EP300KHDRBS1NR3C1SIK2YWHA?/14-3-3
Complex memberships
CRTC2-CREB-CRE complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CRTC2 (TORC2) is sequestered in the cytoplasm under feeding conditions via phosphorylation-dependent interaction with 14-3-3 proteins, and is dephosphorylated and transported to the nucleus in response to fasting/glucagon stimuli where it enhances CREB-dependent transcription of gluconeogenic genes. AMPK activation promotes CRTC2 phosphorylation and blocks its nuclear accumulation, attenuating gluconeogenesis. Subcellular fractionation, reporter assays, adenoviral overexpression/knockdown in mice, pharmacological AMPK activation Nature High 16148943
2004 Under resting conditions, CRTC2 is sequestered in the cytoplasm via phosphorylation-dependent interaction with 14-3-3 proteins. The calcium-regulated phosphatase calcineurin and the Ser/Thr kinase SIK2 both associate with CRTC2. Calcium influx activates calcineurin to dephosphorylate CRTC2, while cAMP inhibits SIK2 kinase activity; together these signals promote CRTC2 nuclear entry and CREB coactivation. Co-immunoprecipitation, subcellular localization imaging, kinase assays, calcineurin inhibitor studies, SIK2 knockdown Cell High 15454081
2007 Insulin promotes phosphorylation and ubiquitin-dependent degradation of CRTC2 via induction of SIK2, which undergoes AKT2-mediated phosphorylation at Ser358. Activated SIK2 stimulates Ser171 phosphorylation and cytoplasmic translocation of CRTC2. Phosphorylated CRTC2 is degraded by the 26S proteasome through an association with COP1, an E3 ligase substrate receptor that promotes CRTC2 ubiquitination at Lys628. In vivo mouse studies, co-immunoprecipitation, site-directed mutagenesis (Ser171, Ser358, Lys628), ubiquitination assays, proteasome inhibitor experiments Nature High 17805301
2009 CRTC2 functions as a dual sensor for ER stress and fasting signals. Acute ER stress triggers dephosphorylation and nuclear entry of CRTC2, which promotes expression of ER quality control genes through an association with ATF6α. ATF6α also disrupts the CREB-CRTC2 interaction, inhibiting CRTC2 occupancy over gluconeogenic genes and reducing hepatic glucose output. Co-immunoprecipitation, chromatin immunoprecipitation, adenoviral knockdown/overexpression in mouse liver, reporter assays Nature High 19543265
2008 Glucose regulates CRTC2 phosphorylation at Ser275, a 14-3-3 binding site, in addition to the known Ser171 site. Calcineurin dephosphorylates Ser275 in response to glucose influx, and dephosphorylation of Ser275 is essential for both glucose- and cAMP-mediated activation of CREB in beta cells. MARK2, an AMPK family kinase, was identified as a Ser275 kinase. Cell-based kinase screen (180 human kinases), site-directed mutagenesis (Ser275), subcellular localization imaging, calcineurin inhibition, islet studies Proceedings of the National Academy of Sciences of the United States of America High 18626018
2012 The CREB-binding domain (CBD) of CRTC2 folds into a single isolated 28-residue helix that interacts with the CREB bZip domain. The CBD and CREB assemble on the CRE with 2:2:1 stoichiometry. Mutation of relevant bZip residues disrupts CRTC interaction without affecting DNA binding. NMR/structural analysis, mutagenesis, binding affinity measurements, reporter assays Proceedings of the National Academy of Sciences of the United States of America High 23213254
2018 Crystal structures of a complex containing the CRTC2 CREB-binding domain, the CREB bZip domain and CRE-containing DNA revealed that CRTC and CREB form a 2:2 complex on CRE-containing DNA. CRTC2 interacts with both CREB and DNA through conserved residues, and the CRTC-DNA interaction confers selectivity toward intrinsic DNA shape. Structure-guided mutagenesis confirmed both interactions are required for complex assembly and CREB stabilization on DNA. X-ray crystallography, structure-guided mutagenesis, functional reporter assays Journal of molecular biology High 29733854
2015 CRTC2 functions as a mediator of mTOR signaling to modulate COPII-dependent SREBP1 processing for lipid synthesis. CRTC2 competes with Sec23A (COPII subunit) to interact with Sec31A (another COPII subunit), disrupting SREBP1 ER-to-Golgi transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. Co-immunoprecipitation, competition binding assays, adenoviral overexpression of mTOR-defective CRTC2 mutant in obese mice, SREBP1 processing assays Nature High 26147081
2010 CRTC2 stimulates hepatic gene expression through an N-terminal CREB binding domain that enhances CREB occupancy over relevant gluconeogenic promoters. CRTC2 knockout mice have decreased circulating glucose during fasting due to attenuation of the gluconeogenic program. Genetic knockout mouse model, chromatin immunoprecipitation, reporter assays, glucose tolerance tests Proceedings of the National Academy of Sciences of the United States of America High 20133702
2009 CRTC2 hyperactivation in the liver upregulates LIPIN1, a mammalian phosphatidic acid phosphatase for DAG synthesis, which then disturbs hepatic insulin signaling via DAG-PKCε activation. TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1. Adenoviral overexpression/knockdown in mouse liver, DAG and PKCε activity measurements, genetic rescue experiments Cell metabolism Medium 19254569
2010 Pin1 associates with CRTC2 at Ser136 (located in the nuclear localization signal) and promotes cytoplasmic translocation of CRTC2, thereby suppressing CRE transcriptional activity. CRTC2 associated with Pin1 does not bind to CREB. Co-immunoprecipitation (endogenous and overexpressed), site-directed mutagenesis (Ser136), subcellular localization imaging, siRNA knockdown, adenoviral gene transfer in diabetic mice The Journal of biological chemistry Medium 20675384
2015 CRTC2 functions as a coactivator for the glucocorticoid receptor (GR) in addition to CREB. CRTC2 physically interacts with the ligand-binding domain of GR through a region spanning amino acids 561–693, and is required for GR-induced transcription of gluconeogenic genes (G6P, PEPCK). Co-immunoprecipitation, domain mapping with deletion mutants, chromatin immunoprecipitation, reporter assays, knockout mouse studies Molecular endocrinology (Baltimore, Md.) Medium 26652733
2015 CRTC2 promotes Th17 cell differentiation via the CREB pathway in response to PGE2. Following dephosphorylation, CRTC2 stimulates expression of IL-17A and IL-17F by binding to CREB at both promoters. CRTC2-mutant mice have decreased Th17 cell numbers and are protected from experimental autoimmune encephalitis. Chromatin immunoprecipitation, CRTC2 knockout mouse model, Th17 differentiation assays, EAE model Nature communications Medium 26031354
2009 CRTC2 nuclear localization and activity is regulated by AMPK-mediated phosphorylation in hypothalamic neurons. Glucose regulates hypothalamic CRTC2 activity via AMPK, and CRTC2 occupancy of the Irs2 promoter controls its expression. CRTC2 is required for appropriate expression of specific hypothalamic CRE genes. Subcellular fractionation, chromatin immunoprecipitation, adenoviral siRNA knockdown, metabolic assays EMBO reports Medium 19713961
2009 CRTC2 is required for CREB target gene activation in islet beta cells. CRTC2 activation is achieved by physiological increases in glucose via calcineurin-mediated dephosphorylation at Ser171 and Ser275. Constitutively active CRTC2 (S171A/S275A) rescues CREB target gene activation when calcineurin is inhibited by immunosuppressants. Site-directed mutagenesis (Ser171, Ser275), insulin secretion assays, glucose-stimulated reporter assays, calcineurin inhibitor experiments, beta cell survival assays Endocrinology Medium 23677932
2019 CRTC2 is constitutively unphosphorylated and activated in LKB1-mutant NSCLC, where it promotes tumor growth via induction of ID1, a CREB target gene. LKB1 loss causes SIK inactivation leading to CRTC2 activation. Genetic analysis of LKB1-mutant cells, shRNA knockdown, chromatin immunoprecipitation, tumor growth assays Science advances Medium 31355336
2009 TORC2 (CRTC2) interacts with the EBV BZLF1 protein through both CREB-binding and BZLF1-dependent mechanisms, and is recruited to the BZLF1 promoter (Zp). Calcineurin-dependent dephosphorylation of TORC2 promotes its nuclear translocation to viral replication compartments and activation of viral lytic replication. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, RNAi knockdown, immunofluorescence localization The Journal of biological chemistry Medium 19164291
2006 CRTC2 (TORC2) physically interacts with HTLV-1 Tax protein and functions as a coactivator for Tax-dependent activation of HTLV-1 LTR. TORC coactivation requires CREB and depletion of TORC1/2/3 inhibited Tax activity. TORC coactivation can be further enhanced by p300. Co-immunoprecipitation, reporter assays, siRNA knockdown, luciferase assays Journal of virology Medium 16809310
2010 TORC2 (CRTC2) cooperates with phosphorylated CREB and p300 to activate CRE-dependent cyclin D1 transcription in response to HTLV-1 Tax. Tax-pCREB complex recruits p300, and TORC2 further enhances p300 recruitment to the cyclin D1 promoter. In vitro binding assays, chromatin immunoprecipitation, reporter assays, co-immunoprecipitation Oncogene Medium 20101207
2023 LKB1 loss triggers elevated CRTC2-CREB signaling downstream of salt-inducible kinases (SIKs), increasing inflammatory gene expression. Mechanistically, CRTC2 cooperates with histone acetyltransferases CBP/p300 to deposit H3K27ac marks at inflammatory gene loci (cytokine/chemokine genes), promoting cytokine expression. This defines an anti-inflammatory program regulated by LKB1 through CRTC2-dependent histone modification. ChIP-seq, H3K27ac profiling, CRTC2 knockdown/overexpression, LKB1 knockout cells, cytokine secretion assays, co-immunoprecipitation with CBP/p300 Molecular cell High 37172591
2021 Sam68 interacts with CRTC2, reduces CRTC2 ubiquitination, and stabilizes CRTC2 protein (not mRNA) levels, thereby promoting hepatic gluconeogenesis. Sam68 truncation mutants lacking C-terminal (Sam68ΔC) or N-terminal (Sam68ΔN) domains fail to bind CRTC2 or stabilize CRTC2 protein respectively. Co-immunoprecipitation, domain-mapping with deletion mutants, ubiquitination assays, global and hepatic Sam68 KO mice, gluconeogenesis assays Nature communications Medium 34099657
2014 Glucagon activates the CREB/CRTC2 transcriptional complex, which is recruited to the Bmal1 promoter to induce its expression. CRTC2 is required for basal transcriptional regulation of Bmal1 as demonstrated by adenovirus-mediated CRTC2 RNAi knockdown and primary Crtc2 null hepatocytes. Insulin suppresses fasting-induced Bmal1 expression by inhibiting CRTC2 activity. Chromatin immunoprecipitation, adenoviral RNAi knockdown, Crtc2 null primary hepatocytes, reporter assays The Journal of biological chemistry Medium 25480789
2012 CRTC2 dephosphorylation and nuclear translocation mediated by FSH-induced calcineurin activation promotes steroidogenic gene expression (StAR, P450scc, 3β-HSD) in granulosa cells. TGFβ1 augments FSH action through calcineurin in a PKA-independent manner. ChIP confirmed CRTC2, CREB, and CBP binding to steroidogenic gene promoters. Chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescence, calcineurin inhibitor studies, progesterone synthesis assays Journal of cellular physiology Medium 21826657
2015 Loss of CRTC2 results in deficiency in DNA mismatch repair (MMR) and increased mutation frequency. CRTC2, together with CREB1 and CBP, directly activates transcription of MMR genes including EXO1, MSH6, PMS1, and POLD2. CRTC2 knockdown/overexpression, chromatin immunoprecipitation, mutation frequency assays, MMR gene expression analysis, patient sample analysis Cell reports Medium 26004186
2020 FXR overexpression in hippocampal CA1 induces cytoplasmic translocation of CRTC2, thereby disrupting CREB-BDNF signaling and producing depression-like behaviors. FXR shRNA prevented CUS-induced cytoplasmic translocation of CRTC2. CRTC2 overexpression and shRNA abrogated the regulatory effect of FXR manipulations on depression-like behaviors, placing CRTC2 downstream of FXR in this pathway. Viral-mediated gene transfer (FXR overexpression/shRNA, CRTC2 overexpression/shRNA), co-immunoprecipitation, immunofluorescence, behavioral testing The international journal of neuropsychopharmacology Medium 32453814
2022 ER stress reduces nuclear levels of CRTC2 in skeletal muscle via mTOR/S6K1 signaling. The mTOR inhibitor torin 1 restored CRTC2 and PGC-1α protein levels. siRNA against S6K1 (an mTORC1 downstream target) prevented the ER-stress-induced reduction in CRTC2 and PGC-1α expression, placing CRTC2 downstream of mTORC1-S6K1 in this pathway. siRNA knockdown of S6K1, mTOR inhibitor (torin 1), Western blot, nuclear fractionation, human myotubes and mouse skeletal muscle Cell communication and signaling : CCS Medium 35428325
2018 CRTC2 controls GLP-1 secretion in intestinal L cells by transcriptionally regulating not only proglucagon but also PC1/3 (the endopeptidase for GLP-1 maturation) and PGC-1α (regulating mitochondrial ATP production and calcium levels required for exocytosis). Intestine-specific CRTC2 KO mice display reduced GLP-1 levels, impaired glucose tolerance, and decreased pancreatic β cells. Intestine-specific CRTC2 KO mice, chromatin immunoprecipitation, reporter assays, GLP-1 secretion assays, ATP/calcium measurements FASEB journal Medium 29118086
2017 Hepatic CRTC2 negatively regulates the Sirt1/Pparα/Fgf21 axis by inducing miR-34a expression, thereby controlling whole-body energy metabolism. Liver-specific CRTC2 KO reduces miR-34a, which increases Sirt1/Pparα activity and hepatic/plasma Fgf21. Ectopic expression of miR-34a reverses the metabolic changes in KO liver. Liver-specific CRTC2 KO mice, miR-34a overexpression (rescue), metabolic phenotyping, ChIP for CREB/CRTC2 at miR-34a locus Nature communications Medium 29192248
2009 VIP activates HCMV MIE gene expression through the PKA-CREB-TORC2 signaling cascade. VIP induces PKA-dependent CRTC2 Ser171 dephosphorylation and nuclear entry. A CRTC2 S171A mutant (devoid of Ser171 phosphorylation) exhibits enhanced nuclear entry and desilences MIE genes in the absence of VIP stimulation. Site-directed mutagenesis (Ser171), nuclear localization imaging, reporter assays, PKA inhibitor studies Journal of virology Medium 19369332
2014 Metformin inhibits StAR expression in endometriotic stromal cells by increasing AMPK phosphorylation, which prevents nuclear translocation of CRTC2 and disrupts formation of the CREB-CRTC2 complex, thereby inhibiting transcription of StAR by reducing CREB-CRTC2 binding to the StAR promoter CRE. Co-immunoprecipitation, chromatin immunoprecipitation, subcellular localization imaging, AMPK activation assays, CRTC2 localization by Western blot The Journal of clinical endocrinology and metabolism Medium 24823468
2020 PFOS decreases interaction between CREB and CRTC2 and binding of CREB/CRTC2 to the StAR promoter region via activation of p38 MAPK and PKA pathways, leading to decreased testosterone biosynthesis. Co-immunoprecipitation, chromatin immunoprecipitation, Western blot, inhibitors (SB203580 for p38, H89 for PKA), in vivo and in vitro models Toxicology Low 33359577
2018 mTORC1 suppresses COX-2 expression in adipocytes by phosphorylating CRTC2, causing dissociation of CREB from the cox-2 promoter. Adipose-specific Raptor depletion relieves this suppression, promoting COX-2-derived prostaglandin synthesis and beige adipogenesis. Adipose-specific Raptor KO mice, adenoviral CRTC2 overexpression, chromatin immunoprecipitation, COX-2 reporter assays Cell reports Medium 30232001
2017 TSH activates CRTC2 via TSHR/cAMP/PKA pathway: TSH stimulates CRTC2 dephosphorylation and increases CRTC2 expression. CRTC2 forms a complex with CREB, and this complex drives hepatic gluconeogenic gene expression. Deletion of TSHR reduces levels of the CRTC2:CREB complex in mouse livers. Co-immunoprecipitation, reporter assays (PEPCK-luciferase), siRNA knockdown, Western blot, TSHR KO mice Molecular and cellular endocrinology Medium 28212844

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 819 16148943
2004 The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 550 15454081
2008 Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. The EMBO journal 516 18566587
2006 Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes & development 411 17043309
2009 Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes & development 338 19240135
2007 Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 327 17805301
2015 The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 259 26147081
2009 The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 247 19543265
2009 TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Molecular biology of the cell 165 19144819
2009 Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS biology 158 19260765
2008 PIP3-independent activation of TorC2 and PKB at the cell's leading edge mediates chemotaxis. Current biology : CB 151 18635356
2006 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proceedings of the National Academy of Sciences of the United States of America 149 16627617
2014 TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. eLife 147 25279700
2016 TORC2 Structure and Function. Trends in biochemical sciences 140 27161823
2010 Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 134 20133702
2010 A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Developmental cell 126 20493808
2006 The phosphatidylinositol 4,5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation. Molecular and cellular biology 117 16847337
2012 Plasma membrane recruitment and activation of the AGC kinase Ypk1 is mediated by target of rapamycin complex 2 (TORC2) and its effector proteins Slm1 and Slm2. Proceedings of the National Academy of Sciences of the United States of America 116 22307609
2005 The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2. Molecular biology of the cell 112 15689497
2010 Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis. The Journal of cell biology 110 20660630
2010 GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. Journal of lipid research 110 20693566
2013 A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma. PLoS genetics 109 23459592
2012 Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. Diabetes 109 22688332
2010 Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 102 20686120
2008 Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proceedings of the National Academy of Sciences of the United States of America 99 18626018
2009 CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. Cell metabolism 81 19583954
2009 TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1. Cell metabolism 77 19254569
2015 TORC1 and TORC2 work together to regulate ribosomal protein S6 phosphorylation in Saccharomyces cerevisiae. Molecular biology of the cell 74 26582391
2012 Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2. Proceedings of the National Academy of Sciences of the United States of America 74 23213254
2013 TORC2 signaling pathway guarantees genome stability in the face of DNA strand breaks. Molecular cell 73 24035500
2015 Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats. World journal of gastroenterology 71 26167077
2009 The induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the coactivators CREB-binding protein and TORC2 and autocrine PGE2. Journal of immunology (Baltimore, Md. : 1950) 67 19564345
2011 The reverse, but coordinated, roles of Tor2 (TORC1) and Tor1 (TORC2) kinases for growth, cell cycle and separase-mediated mitosis in Schizosaccharomyces pombe. Open biology 65 22645648
2017 The TORC2-Dependent Signaling Network in the Yeast Saccharomyces cerevisiae. Biomolecules 61 28872598
2009 Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes. American journal of physiology. Endocrinology and metabolism 60 19706791
2014 Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein. The Journal of biological chemistry 59 25480789
2011 Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation. The Journal of biological chemistry 57 22139837
2006 TORC1 and TORC2 coactivators are required for tax activation of the human T-cell leukemia virus type 1 long terminal repeats. Journal of virology 57 16809310
2018 Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway. Cell reports 56 30232001
2016 The small GTPases Ras and Rap1 bind to and control TORC2 activity. Scientific reports 50 27172998
2020 Perfluorooctane sulfonate (PFOS) disrupts testosterone biosynthesis via CREB/CRTC2/StAR signaling pathway in Leydig cells. Toxicology 49 33359577
2017 Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis. Nature communications 49 29192248
2017 Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2. Molecular and cellular endocrinology 47 28212844
2015 CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis. Molecular endocrinology (Baltimore, Md.) 47 26652733
2019 TORC2 controls endocytosis through plasma membrane tension. The Journal of cell biology 46 31123183
2015 Down-regulation of TORC2-Ypk1 signaling promotes MAPK-independent survival under hyperosmotic stress. eLife 46 26274562
2015 The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nature communications 45 26031354
2018 Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans. PLoS genetics 44 29415022
2017 Cell Size and Growth Rate Are Modulated by TORC2-Dependent Signals. Current biology : CB 43 29290562
2014 Glucose activates TORC2-Gad8 protein via positive regulation of the cAMP/cAMP-dependent protein kinase A (PKA) pathway and negative regulation of the Pmk1 protein-mitogen-activated protein kinase pathway. The Journal of biological chemistry 43 24928510
2019 Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263. International journal of molecular sciences 42 31487963
2012 TORC2 signaling is antagonized by protein phosphatase 2A and the Far complex in Saccharomyces cerevisiae. Genetics 41 22298706
2017 TORC1 and TORC2 converge to regulate the SAGA co-activator in response to nutrient availability. EMBO reports 40 29079657
2010 Chemotactic activation of Dictyostelium AGC-family kinases AKT and PKBR1 requires separate but coordinated functions of PDK1 and TORC2. Journal of cell science 40 20200230
2019 CRTC2 Is a Key Mediator of Amino Acid-Induced Milk Fat Synthesis in Mammary Epithelial Cells. Journal of agricultural and food chemistry 39 31475823
2015 TORC2 mediates the heat stress response in Drosophila by promoting the formation of stress granules. Journal of cell science 39 26054799
2019 The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non-small cell lung cancer. Science advances 38 31355336
2018 CREB/CRTC2 controls GLP-1-dependent regulation of glucose homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 29118086
2009 TORC2, a coactivator of cAMP-response element-binding protein, promotes Epstein-Barr virus reactivation from latency through interaction with viral BZLF1 protein. The Journal of biological chemistry 37 19164291
2017 A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2. Hepatology (Baltimore, Md.) 36 28395113
2012 TORC2 and the AGC kinase Gad8 regulate phosphorylation of the ribosomal protein S6 in fission yeast. Biology open 36 23213482
2016 A PP2A-B55-Mediated Crosstalk between TORC1 and TORC2 Regulates the Differentiation Response in Fission Yeast. Current biology : CB 35 28041796
2014 Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and delaying DNA repair in prostate cancer models. The Prostate 35 24715588
2014 Metformin inhibits StAR expression in human endometriotic stromal cells via AMPK-mediated disruption of CREB-CRTC2 complex formation. The Journal of clinical endocrinology and metabolism 35 24823468
2012 LST8 regulates cell growth via target-of-rapamycin complex 2 (TORC2). Molecular and cellular biology 35 22493059
2010 The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription. Oncogene 35 20101207
2020 The flipside of the TOR coin - TORC2 and plasma membrane homeostasis at a glance. Journal of cell science 34 32393676
2009 Breaking human cytomegalovirus major immediate-early gene silence by vasoactive intestinal peptide stimulation of the protein kinase A-CREB-TORC2 signaling cascade in human pluripotent embryonal NTera2 cells. Journal of virology 34 19369332
2007 Single nucleotide polymorphisms in genes encoding LKB1 (STK11), TORC2 (CRTC2) and AMPK alpha2-subunit (PRKAA2) and risk of type 2 diabetes. Molecular genetics and metabolism 34 17950019
2020 Farnesoid X Receptor-Mediated Cytoplasmic Translocation of CRTC2 Disrupts CREB-BDNF Signaling in Hippocampal CA1 and Leads to the Development of Depression-Like Behaviors in Mice. The international journal of neuropsychopharmacology 33 32453814
2013 Potent dual inhibitors of TORC1 and TORC2 complexes (KU-0063794 and KU-0068650) demonstrate in vitro and ex vivo anti-keloid scar activity. The Journal of investigative dermatology 33 23303455
2013 TORC2 is required to maintain genome stability during S phase in fission yeast. The Journal of biological chemistry 33 23703609
2014 TORC2-a new player in genome stability. EMBO molecular medicine 32 24992933
2012 TOR complex 2 (TORC2) in Dictyostelium suppresses phagocytic nutrient capture independently of TORC1-mediated nutrient sensing. Journal of cell science 32 22266904
2009 A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation. EMBO reports 32 19713961
2013 CRTC2 is required for β-cell function and proliferation. Endocrinology 31 23677932
2012 Plasma membrane proteins Slm1 and Slm2 mediate activation of the AGC kinase Ypk1 by TORC2 and sphingolipids in S. cerevisiae. Cell cycle (Georgetown, Tex.) 31 22895050
2010 Pin1 associates with and induces translocation of CRTC2 to the cytosol, thereby suppressing cAMP-responsive element transcriptional activity. The Journal of biological chemistry 31 20675384
2017 The Stress-Sensing TORC2 Complex Activates Yeast AGC-Family Protein Kinase Ypk1 at Multiple Novel Sites. Genetics 30 28739659
2009 Assays for chemotaxis and chemoattractant-stimulated TorC2 activation and PKB substrate phosphorylation in Dictyostelium. Methods in molecular biology (Clifton, N.J.) 30 19763972
2019 RNA-seq reveal role of bovine TORC2 in the regulation of adipogenesis. Archives of biochemistry and biophysics 29 31893525
2015 Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2. The Journal of biological chemistry 28 26342077
2015 Co-administration of the mTORC1/TORC2 inhibitor INK128 and the Bcl-2/Bcl-xL antagonist ABT-737 kills human myeloid leukemia cells through Mcl-1 down-regulation and AKT inactivation. Haematologica 28 26452980
2013 Tuberous sclerosis complex regulates Drosophila neuromuscular junction growth via the TORC2/Akt pathway. Human molecular genetics 28 23393158
2013 Chemical genetics of rapamycin-insensitive TORC2 in S. cerevisiae. Cell reports 27 24360963
2009 Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis. Experimental & molecular medicine 27 19381067
2018 Who does TORC2 talk to? The Biochemical journal 26 29794170
2014 Calcineurin and CRTC2 mediate FSH and TGFβ1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells. Journal of molecular endocrinology 26 25057110
2012 CREB coactivator CRTC2/TORC2 and its regulator calcineurin crucially mediate follicle-stimulating hormone and transforming growth factor β1 upregulation of steroidogenesis. Journal of cellular physiology 26 21826657
2022 Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2. Cell communication and signaling : CCS 25 35428325
2013 The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. Urologic oncology 25 24054871
2023 LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation. Molecular cell 24 37172591
2020 Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism? Diabetes & metabolism journal 24 32174060
2018 Structural Insights into the CRTC2-CREB Complex Assembly on CRE. Journal of molecular biology 24 29733854
2021 Sam68 promotes hepatic gluconeogenesis via CRTC2. Nature communications 23 34099657
2015 Stimulation of StAR expression by cAMP is controlled by inhibition of highly inducible SIK1 via CRTC2, a co-activator of CREB. Molecular and cellular endocrinology 23 25662274
2015 The CREB Coactivator CRTC2 Is a Lymphoma Tumor Suppressor that Preserves Genome Integrity through Transcription of DNA Mismatch Repair Genes. Cell reports 23 26004186
2015 Saponarin activates AMPK in a calcium-dependent manner and suppresses gluconeogenesis and increases glucose uptake via phosphorylation of CRTC2 and HDAC5. Bioorganic & medicinal chemistry letters 23 26471090
2015 TORC2: a novel target for treating age-associated memory impairment. Scientific reports 23 26489398
2016 Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy. The Journal of cell biology 22 27899413

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