Alternative titles; symbols
HGNC Approved Gene Symbol: SIK2
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38): 11:111,602,449-111,730,855 (from NCBI)
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned SIK2, which they designated KIAA0781. The SIK2 transcript contains 2 repetitive elements in the 3-prime UTR. RT-PCR ELISA detected moderate to high expression in all tissues examined. Highest expression was in kidney, followed in order by brain, ovary, heart, lung, skeletal muscle, pancreas, testis, and spleen.
Horike et al. (2003) cloned mouse Sik2. The deduced 931-amino acid protein has a calculated molecular mass of about 120 kD. Sik2 contains an N-terminal serine/threonine protein kinase domain, a central domain with a ubiquitin-associate motif, and a C-terminal protein kinase A (see 176911) phosphorylation site. Northern blot analysis of several mouse tissues detected transcripts of 4.0 and 6.0 kb. Highest expression was in white adipose and brown adipose tissues. Testis showed intermediate Sik2 expression, and much lower expression was found in all other tissues examined. Fluorescence-labeled Sik2 was expressed mostly in the cytoplasm of transfected mouse preadipocytes.
Horike et al. (2003) found that mouse Sik2 could repress cAMP-responsive element-dependent transcription in a reporter gene assay. When mouse preadipocytes were treated with an adipose differentiation mixture, Sik2 mRNA was induced coincident with the induction of CEBP-beta (189965) mRNA. Sik2 could phosphorylate ser794 of human insulin receptor substrate-1 (IRS1; 147545) following coexpression in COS cells. Overexpression of Sik2 in adipocytes elevated the phosphorylation of mouse Irs1 on the equivalent serine residue. Finally, the activity and content of Sik2 was elevated in white adipose tissue of db/db diabetic mice (see 601007). Horike et al. (2003) concluded that, in insulin-stimulated adipocytes, SIK2 phosphorylates IRS1 at ser794 and may modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance associated with diabetes.
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 (608972), a CREB coactivator. This module consisted of the calcium-regulated phosphatase calcineurin (see 114105) and SIK2, 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.
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.
By genomic sequence analysis, Katoh and Katoh (2003) mapped the SNF1LK2 gene to chromosome 11q23.1.
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]
Horike, N., Takemori, H., Katoh, Y., Doi, J., Min, L., Asano, T., Sun, X. J., Yamamoto, H., Kasayama, S., Muraoka, M., Nonaka, Y., Okamoto, M. Adipose-specific expression, phosphorylation of ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J. Biol. Chem. 278: 18440-18447, 2003. [PubMed: 12624099] [Full Text: https://doi.org/10.1074/jbc.M211770200]
Katoh, M., Katoh, M. Identification and characterization of human KIAA1391 and mouse Kiaa1391 genes encoding novel RhoGAP family proteins with RA domain and ANXL repeats. Int. J. Oncol. 23: 1471-1476, 2003. [PubMed: 14532992]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
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]