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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CRTC2 (CREB regulated transcription coactivator 2) Kristy A Brown, Nirukshi Samarageewa Prince Henry's Institute, Clayton, Victoria, 3168, Australia (KAB, NS) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/CRTC2ID50581ch1q21.html DOI: 10.4267/2042/44907 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. Identity Other names: TORC2, RP11-422P24.6 HGNC (Hugo): CRTC2 Location: 1q21.3 Function Transcriptional coactivator for CREB (cAMPresponsive 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 proteincoupled receptors, and AMPK/SIKs. DNA/RNA Description 10,893 bases; on minus strand. Includes 14 exons. Transcription Transcript measures 2598 bp with a 2082 bp coding sequence. Implicated in Protein Peutz-Jeghers syndrome Description Note Peutz-Jeghers syndrome (PJS) is an autosomaldominant 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. 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- Oestrogen-receptor (ER) positive breast cancer Note The increased prevalence of oestrogen-dependent, postmenopausal breast cancers is correlated with activated protein kinase (AMPK) and the salt-inducible kinases (SIKs). Dephosphorylated CRTC2 readily translocates to the nucleus. CRTC2 contains a nuclear Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1104 CRTC2 (CREB regulated transcription coactivator 2) Brown KA, Samarageewa N Okamoto M, Montminy M. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell. 2004 Oct 1;119(1):61-74 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. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137-63 Katoh Y, Takemori H, Lin XZ, Tamura M, Muraoka M, Satoh T, Tsuchiya Y, Min L, Doi J, Miyauchi A, Witters LA, Nakamura H, Okamoto M. Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade. FEBS J. 2006 Jun;273(12):2730-48 Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol. 2006 Dec;18(6):598-608 Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC. Transducer of regulated CREB-binding proteins (TORCs) induce PGC1alpha transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):1437984 Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR, Simpson ER. Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Res. 2009 Jul 1;69(13):53929 References Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB, Montminy M. TORCs: transducers of regulated CREB activity. Mol Cell. 2003 Aug;12(2):413-23 Brown KA, Simpson ER. Obesity and breast cancer: progress to understanding the relationship. Cancer Res. 2010 Jan 1;70(1):4-7 Sofi M, Young MJ, Papamakarios T, Simpson ER, Clyne CD. Role of CRE-binding protein (CREB) in aromatase expression in breast adipose. Breast Cancer Res Treat. 2003 Jun;79(3):399-407 This article should be referenced as such: Brown KA, Samarageewa N. CRTC2 (CREB regulated transcription coactivator 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1104-1105. Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1105