Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation

Abstract Insulin like growth factor (IGF) signaling plays an important role in cell growth and proliferation and implicated in regulation of cancer, metabolism and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through Cryptochromes (CRYs), transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry deficient mice and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement with that, Cry-deficient mice have reduced body (about 30% reduction) and organ size. Down regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone induced JAK2 kinase mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on JAK2 dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus, CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation which provides the mechanism for circadian rhythms in IGF signaling in vivo.