Figure 3. Circadian control of intracellular signaling.

The central pacemaker controlled autonomic nervous and neuroendocrine systems (ANS and NES) rhythmically signal to all of their target tissues. The resulting circadian rhythm in peripheral tissue function also generates local and/or circulating signaling molecules that rhythmically act on their targets. Together, these extracellular signals including neurotransmitters, steroid hormones, peptide hormones, chemokines, growth factors and cytokines activate intracellular signaling mediated by G-protein coupled receptors (GPCRs), tyrosine kinase receptors, integrins (not shown), and nuclear receptors in a tissue and cell-type specific manner. These same intracellular signaling pathways also activate the peripheral clock. The coordinated activities of the central and peripheral clocks orchestrate the complicated extracellular and intracellular signaling to maintain tissue homeostasis by controlling a network of gene expression. Disruption of the central clock-controlled extracellular signaling or mutations in core circadian genes both abolish peripheral clock activity leading to loss of circadian homeostasis in peripheral tissues. The representative intracellular signaling pathways directly or indirectly controlled by the central clock shown in the figure include the c-AMP/PKA/CREB/AP1, Ras/MARK/JNK/ERK and PI3K/AKT/β-Catenin/TCF/LEF pathways essential for c-Myc activation and cell cycle progression^478–480, the PI3K/AKT/mTOR signaling controlling biosynthesis and drug resistance^451,481, the GPCR/ATM signaling for p53 activation²⁹, the GPCR/PKC/NF-κB pathway that regulates stress and immune response⁴⁸², the JAK/STAT pathway controlling apoptotic response⁴⁸³, and the GR and ERα signaling pathways cross-talking with the AP1 signaling^484,485. These signaling pathways also control the expression and function of circadian genes leading to a coupled activation of the molecular clock with tissue-specific function in vivo including cell proliferation, metabolism, apoptosis, DNA repair, biosynthesis, secretion and senescence^371–374.