The involvement of SIK2 in regulating the metabolisms of lipid and glucose and the stress response

Salt-inducible kinase 2 (SIK2) is a serine/threonine protein kinase belonging to the member of AMP-activated protein kinase subfamily. The highest expression level of SIK2 gene was found in the fatty tissue. SIK2 phosphorylates the cAMP-responsive element-binding protein (CREB)-regulated transcription co-activator 2 and 3 (CRTC2; CRTC3), and negatively regulates the transcription activity of these proteins. SIK2 can also phosphorylate the p300/CBP, which in turn modulates the expression of a series of genes related to gluconeogenesis and lipid synthesis, and regulates the metabolisms of glucose and lipid. The Lys53 of SIK2 is inactivated by p300/CBP-mediated acetylation under the stress of nutritional deficiencies. The sequestrated acetylated SIK2 migrates from the cytosol into the autophagosome. SIK2 regains its kinase activity in autophagosome through deacetylation mediated by histone deacetylase 6 (HDAC6), and is involved in the fusing of autophagosome and lysosome and autophagy processing. Hence, SIK2 is expected to become a new target for the therapy of metabolic syndromes, e.g. obesity and diabetes.