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FLASH GENE
Symbol CRTC2 contributors: mct - updated : 13-04-2015
HGNC name CREB regulated transcription coactivator 2
HGNC id 27301
DNA
TYPE functioning gene
STRUCTURE 10.89 kb     14 Exon(s)
MAPPING cloned Y linked N status provisional
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
14 - 2598 - 693 - 2005 16002396
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveliver   predominantly Homo sapiens
Nervousbrain    
 nervecranial nerve  highly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectivebone  highly
cells
SystemCellPubmedSpeciesStageRna symbol
Nervousneuron
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • an N-terminal coiled-coil domain
  • a protein kinase A phosphorylation site
  • two consensus (PXIXIT) motifs that mediate an association with calcineurin
  • conjugated GlycoP
    HOMOLOGY
    Homologene
    FAMILY
  • TORC family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,nucleus,nucleoplasm
    text
  • sequestered in the cytoplasm through phosphorylation-dependent interaction with 14.3.3 proteins
  • nuclear entry is regulated by cAMP and calcium influx
  • locate primarily in the cytoplasm but have also been reported to shuttle into the nucleus
  • predominantly localized in endoplasmic reticulum
  • basic FUNCTION
  • coactivator mediating cooperatively between cAMP and calcium signal in islet cells
  • controls the organization of the actin cytoskeleton through a rapamycin-insensitive signaling branch
  • SIK2-CRTC2 cascade may be important for the regulation of PPARGC1A and UCP1 gene expression in insulin signaling in brown adipose tissue (BAT)
  • functioning as a dual sensor for ER stress and fasting signals
  • having critical roles in chromatin metabolism and in promoting mitotic entry, most notably after recovery from DNA-damaging conditions
  • plays a role in regulating the actin cytoskeleton and cell wall integrity pathway
  • role in the transcriptional response to fasting, but with only a limited contribution to the maintenance of glucose homeostasis
  • with CRTC1, contribute to the regulation of Na(+) absorption
  • direct role of CRTC2, at least partly through AKT1, in driving tumorigenesis
  • can function cotranslationally by phosphorylating residues in nascent chains that are critical to attain proper conformation
  • CRTC2, like MTOR, functions in translation and has a role in cotranslational folding of nascent cytosolic polypeptides such as AKT1
  • is not part of the initiation complex, but is required for efficient translation
  • role for CRTC2 in the cotranslational phosphorylation of Akt that is required for proper AKT1 folding or maturation
  • regulates neutrophil chemotaxis in a cAMP- and RHOA-dependent fashion
  • regulates invasive cancer cell migration through selective activation of AKT1
  • in association with ribosome promotes the co-translational phosphorylation of AKT1 on its Thr-450 turn motif site
  • its functional activity as the regulatory kinase of AKT1 and its related kinases takes place on the ER surface
  • unique functions of CRTC2 complexes in the induction of type I IFN responses and suggest a critical role for CRTC2-mediated signals in IFN signaling
  • MAPKAP1 and CRTC2 are dispensable for the development and activation of T cells but play a role in natural T-regulatory (nTreg) cells differentiation
  • AKT1-independent relay from CRTC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism
  • PI3K- and insulin-dependent dendritic growth depends on the activation of both MTOR and CRTC2, and MTOR can act downstream of CRTC2 in developing mammalian neurons
  • importance of CRTC2 in controlling cellular insulin sensitivity
  • is essential both for glucose-stimulated insulin secretion and cell survival in the beta-cell
  • SIK2 is critical in regulating whole-body glucose metabolism primarily by controlling the CRTC2-CREB function of the white adipocytes
  • likely participates in CREB-dependent photic entrainment of suprachiasmatic nucleus (SCN) function
  • is a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism
  • CREB coactivators CRTC2 and CRTC3 modulate bone marrow hematopoiesis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with 14.3.3 proteins
  • O-glycosylated
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with SIK2
  • PIN1-binding protein (association of PIN1 with CRTC2 to decrease the nuclear CBP/CRTC/CREB complex)
  • MAPKAP1/CRTC2-AKT2 signaling axis is a key regulator of FOXO1 transcriptional activity in B cells
  • can colocalize with actively translating ribosomes and can stably interact with RPL23A, a large ribosomal subunit protein present at the tunnel exit
  • an intact CRTC2 is required for efficient binding of MTOR, and rictor to translating ribosomes
  • interacting with PINK1 (PINK1 enhanced the phosphorylation level of AKT1 via activation of CRTC2)
  • interacting with NIP7 (NIP7 controls CRTC2 via its role in ribosome maturation)
  • activation of AKT1 through CRTC2 and PREX1, that regulates cancer cell migration, invasion and metastasis)
  • RAC1 is a critical regulator of both MTOR and CRTC2 in response to growth-factor stimulation (binding of RAC1 to MTOR does not depend on the GTP-bound state of RAC1, but on the integrity of its C-terminal domain)
  • MAPKAP1 mediates SGK1 protein interaction with CRTC2 protein complex and is required for selective activation of the epithelial sodium channel
  • MAPKAP1 serves as a selectivity adaptor for the recruitment of CRTC2 targets
  • modulated negatively by interaction with DEPTOR and positively by the TSC1-TSC2 protein complex
  • CRTC2 is crucial for NOTCH1 signaling to regulate AKT1 and NFKB1
  • ITPR1, ITPR2 enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2
  • associate with ITPR1 via its N-terminal CREB binding domain (CBD)
  • CRTC2 can regulate insulin signaling at the level of insulin receptor substrate-1 (IRS1)
  • CRTC2 negatively feeds back to IRS1 via control of FBXW8 stability and localization
  • CRTC2 functions in the regulation of FBXW8 that allows FBXW8 to mediate IRS1 turnover following insulin stimulation
  • UCHL1 is a key regulator of the dichotomy between MTOR and CRTC2 signaling
  • CCDC28B plays a role in CRTC2 assembly and/or stability
  • phosphorylates the hydrophobic motif site Ser473 on the Ser/Thr kinase AKT1 that is necessary for its activation
  • ARHGEF3 negatively regulates cell survival and skeletal myoblast differentiation by inhibiting CRTC2 and subsequently the Ser/Thr kinase AKT1
  • in cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme-encoding genes
  • beta-agonists or catecholamines released during intense exercise induce CREB-mediated transcriptional programs through activation of its obligate coactivators CRTC2 and CRTC3
  • SIK2 increases SLC2A4 levels, regulates CRTC2, CRTC3, HDAC4 and glucose uptake in adipocytes
  • cell & other
  • CRTC2-ribosome interaction promotes Akt signaling in cancer cells, and CRTC2-ribosome association is important in oncogenic PI3K signaling
  • REGULATION
    activated by dephosphorylation upon an increase in ER stress, leading to its nuclear entry where it promotes the expression of ER quality control genes
    ribosomes that activate CRTC2 directly, and ribosome association appears to be a major if not the sole mechanism of CRTC2 activation
    glucagon that stimulates CRTC2 dephosphorylation via activation of ITPR1, ITPR2
    Other activation of CRTC2 plays a pivotal role in cardioprotection
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    hepatic CRTC2 activity is elevated in obesity
    constitutional       gain of function
    hyperactivation of CRTC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis
    constitutional     --other  
    dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner
    tumoral     --over  
    may play an important role in the development and hereditary of in non-small cell lung cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneoushypertension 
    pharmacological manipulation of CRTC1/2 signalling may provide novel therapies for Na(+)-sensitive hypertension
    diabetetype 2 
    small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes
    cancerhemopathy 
    therapeutic target in multiple myeloma
    cancer  
    cotranslational functions of CRTC2 could be tapped for therapeutics against cancer
    neurologyneurodegenerative 
    cotranslational functions of CRTC2 could be tapped for therapeutics paricularly against diseases caused by protein misprocessing, such as neurodegenerative and aging-related disorders
    cancerskin 
    disrupting the CRTC2-ribosome interaction may be a useful strategy in the treatment of melanomas, colon carcinomas, and possibly other cancers
    ANIMAL & CELL MODELS
    in Crtc2 (-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity