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 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 <i>Cry</i>-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, <i>Cry-</i>deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon <i>Cry</i> deficiency correlates with reduced <i>Igf-1</i> 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 <i>Cry</i>-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon <i>Cry</i> 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.