Alternative titles; symbols
HGNC Approved Gene Symbol: CRTC2
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:153,947,675-153,958,612 (from NCBI)
By searching databases for sequences similar to TORC1 (CRTC1; 607536), Iourgenko et al. (2003) identified TORC2. The deduced 693-amino acid protein contains an N-terminal coiled-coil domain and a protein kinase A (see 176911) phosphorylation site. TORC2 shares 32% amino acid identity with TORC1.
The International Radiation Hybrid Mapping Consortium mapped the CRTC2 gene to chromosome 1 (RH12271).
By cotransfection of TORC2 and reporter genes in HeLa cells, Iourgenko et al. (2003) found that TORC2 potently activated expression of genes driven by the IL8 (146930) promoter or a promoter carrying multiple CRE-like sequences.
Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB (123810). Screaton et al. (2004) identified a signaling module that mediated the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a CREB coactivator. This module consisted of the calcium-regulated phosphatase calcineurin (see 114105) and the ser/thr kinase SIK2 (608973), both of which associated with TORC2. Under resting conditions, TORC2 was sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins (see 601288). Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupted TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increased calcineurin activity, whereas cAMP inhibited SIK2 kinase activity. The results illustrated how a phosphatase/kinase module connects 2 signaling pathways in response to nutrient and hormonal cues.
Koo et al. (2005) showed that hormonal and energy sensing pathways of glucose homeostasis converge on the coactivator TORC2 to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK (see 602739) attenuate the gluconeogenic program by promoting TORC2 phosphorylation and blocking its nuclear accumulation.
Wu et al. (2006) screened a human cDNA expression library for genes that could activate the mouse Pgc1-alpha (PPARGC1A; 604517) promoter following expression in HeLa cells and identified TORC1 (CRTC1; 607536), TORC2, and TORC3 (608986) as potent Pgc1-alpha activators. Forced expression of these TORCs in mouse primary muscle cells induced endogenous Pgc1-alpha and its target genes, resulting in increased mitochondrial oxidative capacity.
Kuraishy et al. (2007) noted that the germinal center (GC) is home to T-cell-independent antigen-driven B-cell maturation and memory B-cell and plasma cell production, and that it is the site of origin for most B-cell lymphomas. TCL1 (186960) expression is highest in immature B cells and lymphomas and low or absent in mature B cells and plasma cells. By sequence and chromatin immunoprecipitation analyses, Kuraishy et al. (2007) identified a CREB response element-like half-site in the TCL1 promoter, and they found that CREB expression supported robust basal activity of the TCL1 promoter. Activation of TCL1 was independent of phosphorylation of ser133 of CREB and was dependent on expression of TORC2 and phosphorylation of ser171 of TORC2. Knockdown of TORC2 resulted in marked repression of TCL1 expression in GC B cells, and confocal microscopy showed that nuclear localization of TORC2 was required for TCL1 expression. Kuraishy et al. (2007) proposed that a CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B-cell development and circumvents oncogenic progression.
Dentin et al. (2007) showed in mice that insulin inhibits gluconeogenic gene expression during refeeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the serine-threonine kinase SIK2, which the authors showed undergoes AKT2-mediated phosphorylation at ser358. Activated SIK2 in turn stimulated the ser171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during refeeding through an association with COP1 (608067), a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at lys628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, Dentin et al. (2007) concluded that their results pointed to an important role for this pathway in the maintenance of glucose homeostasis.
Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT; 300255). Dentin et al. (2008) showed that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cAMP response element-binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase (604039) blocked effects of glucose on gluconeogenesis, demonstrating the importance of the hexosamine biosynthetic pathway in the development of glucose intolerance.
Liu et al. (2008) demonstrated that a fasting-inducible switch, consisting of the histone acetyltransferase p300 (602700) and the nutrient-sensing deacetylase sirtuin-1 (SIRT1; 604479), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1 (136533). After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which Liu et al. (2008) showed is also activated by dephosphorylation at ser89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at lys628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase COP1. Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator Ppar-gamma coactivator 1-alpha (PGC1-alpha; 604517) by SIRT1 activators, Liu et al. (2008) concluded that their results illustrate how the exchange of 2 gluconeogenic regulators during fasting maintains energy balance.
Using mice and primary mouse hepatocytes, Wang et al. (2009) found that Crtc2 functioned as a dual sensor for endoplasmic reticulum (ER) stress and fasting signals. Acute increases in ER stress triggered dephosphorylation and nuclear entry of Crtc2, which in turn promoted expression of ER quality-control genes through an association with activating transcription factor-6 (ATF6; 605537), an integral branch of the unfolded protein response. In addition to mediating Crtc2 recruitment to ER stress-inducible promoters, Atf6 also reduced hepatic glucose output by disrupting the Creb-Crtc2 interaction and thereby inhibiting Crtc2 occupancy over gluconeogenic genes. Conversely, hepatic glucose output was upregulated when hepatic Atf6 protein amounts were reduced, either by RNA interference-mediated knockdown or as a result of persistent stress in obesity. Atf6 overexpression in livers of obese mice reversed Crtc2 effects on the gluconeogenic program and lowered hepatic glucose output. Wang et al. (2009) concluded that crosstalk between ER stress and fasting pathways at the level of the transcriptional coactivator CRTC2 contributes to glucose homeostasis.
Wang et al. (2012) showed in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent ser/thr-phosphatase calcineurin (PPP3CA; 114105). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1, 147265; ITPR2, 600144; ITPR3, 147267), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
Han et al. (2015) showed in mice that CRTC2 functions as a mediator of mTOR (601231) signaling to modulate coat protein complex II (COPII)-dependent Srebp1 (184756) processing. Crtc2 competes with Sec23A (610511), a subunit of the COPII complex, to interact with Sec31A (610257), another COPII subunit, thus disrupting Srebp1 transport. During feeding, mTOR phosphorylates Crtc2 and attenuates its inhibitory effect on COPII-dependent Srebp1 maturation. As hepatic overexpression of an mTOR-defective Crtc2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrated how the transcriptional coactivator Crtc2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.
In conditional knockout mice in which Lkb1 (602216) was deleted in adult liver, Shaw et al. (2005) showed that Torc2, a transcriptional coactivator of CREB, was dephosphorylated and entered the nucleus, driving the expression of Pgc1a, which in turn drives gluconeogenesis. Adenoviral small hairpin RNA for Torc2 reduced Pgc1a expression and normalized blood glucose levels in mice with deleted liver Lkb1, indicating that TORC2 is a critical target of LKB1-AMPK signals in the regulation of gluconeogenesis. Finally, Shaw et al. (2005) showed that metformin, a widely prescribed type 2 diabetes therapy, requires LKB1 in the liver to lower blood glucose levels.
Dentin, R., Hedrick, S., Xie, J., Yates, J., III, Montminy, M. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319: 1402-1405, 2008. [PubMed: 18323454] [Full Text: https://doi.org/10.1126/science.1151363]
Dentin, R., Liu, Y., Koo, S.-H., Hedrick, S., Vargas, T., Heredia, J., Yates, J., III, Montminy, M. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366-369, 2007. [PubMed: 17805301] [Full Text: https://doi.org/10.1038/nature06128]
Han, J., Li, E., Chen, L., Zhang, Y., Wei, F., Liu, J., Deng, H., Wang, Y. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524: 243-246, 2015. [PubMed: 26147081] [Full Text: https://doi.org/10.1038/nature14557]
Iourgenko, V., Zhang, W., Mickanin, C., Daly, I., Jiang, C., Hexham, J. M., Orth, A. P., Miraglia, L., Meltzer, J., Garza, D., Chirn, G.-W., McWhinnie, E., and 9 others. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Nat. Acad. Sci. 100: 12147-12152, 2003. [PubMed: 14506290] [Full Text: https://doi.org/10.1073/pnas.1932773100]
Koo, S.-H., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., Hedrick, S., Xu, W., Boussouar, F., Brindle, P., Takemori, H., Montminy, M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437: 1109-1114, 2005. [PubMed: 16148943] [Full Text: https://doi.org/10.1038/nature03967]
Kuraishy, A. I., French, S. W., Sherman, M., Herling, M., Jones, D., Wall, R., Teitell, M. A. TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation. Proc. Nat. Acad. Sci. 104: 10175-10180, 2007. [PubMed: 17548807] [Full Text: https://doi.org/10.1073/pnas.0704170104]
Liu, Y., Dentin, R., Chen, D., Hedrick, S., Ravnskjaer, K., Schenk, S., Milne, J., Meyers, D. J., Cole, P., Yates, J., III, Olefsky, J., Guarente, L., Montminy, M. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456: 269-273, 2008. [PubMed: 18849969] [Full Text: https://doi.org/10.1038/nature07349]
Screaton, R. A., Conkright, M. D., Katoh, Y., Best, J. L., Canettieri, G., Jeffries, S., Guzman, E., Niessen, S., Yates, J. R., III, Takemori, H., Okamoto, M., Montminy, M. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119: 61-74, 2004. [PubMed: 15454081] [Full Text: https://doi.org/10.1016/j.cell.2004.09.015]
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., Cantley, L. C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642-1646, 2005. [PubMed: 16308421] [Full Text: https://doi.org/10.1126/science.1120781]
Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I., Montminy, M. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485: 128-132, 2012. [PubMed: 22495310] [Full Text: https://doi.org/10.1038/nature10988]
Wang, Y., Vera, L., Fischer, W. H., Montminy, M. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460: 534-537, 2009. [PubMed: 19543265] [Full Text: https://doi.org/10.1038/nature08111]
Wu, Z., Huang, X., Feng, Y., Handschin, C., Feng, Y., Gullicksen, P. S., Bare, O., Labow, M., Spiegelman, B., Stevenson, S. C. Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1-alpha transcription and mitochondrial biogenesis in muscle cells. Proc. Nat. Acad. Sci. 103: 14379-14384, 2006. [PubMed: 16980408] [Full Text: https://doi.org/10.1073/pnas.0606714103]