Salt-inducible kinase 1 was originally identified as a serine/threonine kinase from adrenocortical tissues of rats on a high salt diet. SIK1 is an SNF1/AMPK family kinase capable of autophosphorylation. SIK2 is an isoform of SIK1 and is specifically expressed in adipose tissues where it is induced during adipocyte differentiation. Studies suggest that SIK2 can phosphorylate human insulin receptor substrate 1 at Ser794. Along with evidence that SIK2 expression and activity are increased in white adipocytes of diabetic mice, this finding suggests a possible role for SIK2 in regulating insulin signaling in adipocytes and in the development of insulin resistance. Insulin triggers Akt2-mediated phosphorylation of SIK2 at Ser358 and the resultant kinase activation during post-fasting feeding. The activated SIK2 then induces the phosphorylation of TORC2 at Ser171, resulting in translocation of this transcriptional coactivator from the nucleus to the cytoplasm, where it is degraded through the ubiquitin pathway, leading to inhibition of gluconeogenic gene expression.SIK3 was identified in a screen for tumor-associated antigens that promoted cell proliferation and showed increased expression in ovarian cancer. Analysis of SIK3 knockout mice identified a key role in skeletal development via regulation of subcellular localization of HDAC4. Additional studies have also found that SIK3 can regulate glucose and lipid metabolism in the liver. SIK1 and SIK3 were found to mediate the tumor suppressive activity of LKB1 in models of non-small cell lung cancer.
[1] Wang, Z. et al. (1999) FEBS Lett 453, 135-9.
[2] Horike, N. et al. (2003) J Biol Chem 278, 18440-7.
[3] Katoh, Y. et al. (2004) Mol Cell Endocrinol 217, 109-12.
[4] Dentin, R. et al. (2007) Nature 449, 366-9.
[5] Charoenfuprasert, S. et al. (2011) Oncogene 30, 3570-84.
[6] Sasagawa, S. et al. (2012) Development 139, 1153-63.
[7] Uebi, T. et al. (2012) PLoS One 7, e37803.
[8] Hollstein, P.E. et al. (2019) Cancer Discov 9, 1606-27.
