CRTC2 (CREB regulated transcription coactivator 2)

2010-02-01   Kristy A Brown , Nirukshi Samarageewa 

Prince Henrys Institute, Clayton, Victoria, 3168, Australia

Identity

HGNC
LOCATION
1q21.3
LOCUSID
ALIAS
TORC-2,TORC2
FUSION GENES

DNA/RNA

Description

10,893 bases; on minus strand. Includes 14 exons.

Transcription

Transcript measures 2598 bp with a 2082 bp coding sequence.

Proteins

Description

693 amino acids; 73,302 Da.

Expression

Particularly abundant in B and T lymphocytes. Higher levels were also seen in muscle, lung, spleen, ovary and breast. Lower expressions found in brain, colon, heart, kidney, prostate, small intestine and stomach, with significantly lowest expression in liver and pancreas.

Localisation

Phosphorylation of CRTC2 triggers the phosphorylation-dependent binding to 14-3-3 proteins, and hence sequestration of CRTC2 in the cytosol thereby preventing its nuclear translocation and the activation of CREB. Proteins known to phosphorylate CRTC2 at Ser171 include AMP-activated protein kinase (AMPK) and the salt-inducible kinases (SIKs). Dephosphorylated CRTC2 readily translocates to the nucleus. CRTC2 contains a nuclear localisation sequence (NLS) at amino acids 56-144 as well as two nuclear export sequences (NES1 and NES2) within the region of amino acids 145-320.

Function

Transcriptional coactivator for CREB (cAMP-responsive element binding protein).The highly conserved N-terminal coiled-coil domain of the CRTC2 interacts with the bZip domain of CREB which activates both consensus and variant cAMP response element (CRE) sites, leading to activation of CREB target gene expression. CRTC2 responds to stimulation by cAMP, calcium, fasting hormones, G protein-coupled receptors, and AMPK/SIKs.

Implicated in

Entity name
Peutz-Jeghers syndrome
Note
Peutz-Jeghers syndrome (PJS) is an autosomal-dominant genetic disorder that is characterised by an increased risk of developing malignant tumours. Most of the identified mutations in the LKB1 gene are localised to the catalytic kinase domain so that it is thought that PJS results from loss of LKB1 kinase activity. The silencing of LKB1, leads to the decreased activity of AMPK and SIK and leads to the increased nuclear translocation and activity of CRTC2.
Disease
Gastrointestinal polyps and cancers including esophagus, stomach, small intestine, colon, pancreas, lung, testes, breast, uterus, ovary and cervix.
Entity name
Oestrogen-receptor (ER) positive breast cancer
Note
The increased prevalence of oestrogen-dependent, postmenopausal breast cancers is correlated with elevated local levels of oestrogens as a result of an increase in cytochrome P450 aromatase expression within the adipose stromal (hAS) cells surrounding the breast tumour - aromatase is the enzyme responsible for the conversion of androgens to oestrogens. This is governed by promoter switching from the distal promoter I.4 to the proximal promoter PII on the CYP19A1 gene, that encodes aromatase, in response to factors derived from the tumour such as prostaglandin E2 (PGE2). Interestingly, the LKB1/ AMPK pathway has been shown to inhibit aromatase expression via the cytoplasmic sequestration of CRTC2. However, PGE2 inhibits LKB1/AMPK signaling, leading to the nuclear translocation of CRTC2 and its enhanced binding and activation of aromatase promoter PII in hAS cells. Furthermore, the adipokine leptin, produced at higher levels in obesity, has been shown to cause an increase in CRTC2 nuclear translocation and consequently, in aromatase expression.

Bibliography

Pubmed IDLast YearTitleAuthors
167564882006LKB1-dependent signaling pathways.Alessi DR et al
195092262009Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women.Brown KA et al
200288642010Obesity and breast cancer: progress to understanding the relationship.Brown KA et al
145360812003TORCs: transducers of regulated CREB activity.Conkright MD et al
168179012006Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade.Katoh Y et al
154540812004The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.Screaton RA et al
170462242006Glucose metabolism and cancer.Shaw RJ et al
128464242003Role of CRE-binding protein (CREB) in aromatase expression in breast adipose.Sofi M et al
169804082006Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.Wu Z et al

Other Information

Locus ID:

NCBI: 200186
MIM: 608972
HGNC: 27301
Ensembl: ENSG00000160741

Variants:

dbSNP: 200186
ClinVar: 200186
TCGA: ENSG00000160741
COSMIC: CRTC2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000160741ENST00000303569J3KNE6
ENSG00000160741ENST00000368630Q5T4K5
ENSG00000160741ENST00000368633Q53ET0
ENSG00000160741ENST00000461638H0YDQ8

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90
100

Pathways

PathwaySourceExternal ID
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
Circadian ClockREACTOMER-HSA-400253
Insulin resistanceKEGGhsa04931

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134850491TransplantationDiseaseClinicalAnnotationassociatedPD26644205
PA33744PRKAA1GenePathwayassociated22722338
PA33745PRKAA2GenePathwayassociated22722338
PA33746PRKAB1GenePathwayassociated22722338
PA33747PRKAB2GenePathwayassociated22722338
PA33751PRKAG1GenePathwayassociated22722338
PA33752PRKAG2GenePathwayassociated22722338
PA33753PRKAG3GenePathwayassociated22722338
PA37935SIRT1GenePathwayassociated22722338
PA449167cyclosporineChemicalClinicalAnnotationassociatedPD26644205
PA451578tacrolimusChemicalClinicalAnnotationassociatedPD26644205

References

Pubmed IDYearTitleCitations
169804082006Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.111
174763042007Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression.83
186260182008Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2.52
195092262009Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women.36
168093102006TORC1 and TORC2 coactivators are required for tax activation of the human T-cell leukemia virus type 1 long terminal repeats.34
236711202013PRMT5 modulates the metabolic response to fasting signals.28
232132542012Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2.26
206935662010GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene.20
191642912009TORC2, a coactivator of cAMP-response element-binding protein, promotes Epstein-Barr virus reactivation from latency through interaction with viral BZLF1 protein.19
206753842010Pin1 associates with and induces translocation of CRTC2 to the cytosol, thereby suppressing cAMP-responsive element transcriptional activity.17

Citation

Kristy A Brown ; Nirukshi Samarageewa

CRTC2 (CREB regulated transcription coactivator 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-02-01

Online version: http://atlasgeneticsoncology.org/gene/50581/crtc2