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

Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is 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 -deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon deficiency correlates with reduced 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 the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of -deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon 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.