cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivator (CRTC) (CREB/CRTC)

The cAMP response element-binding protein (CREB) and its coactivators, the CREB-regulated transcription coactivators (CRTCs), form a fundamental transcriptional complex that regulates gene expression in response to cAMP and calcium signaling (UniProt P16220, Q53ET0). CREB binds to specific DNA sequences called cAMP response elements (CREs), while CRTCs enhance CREB's transcriptional activity following their signal-induced translocation from the cytoplasm to the nucleus. This signaling axis is critical for maintaining physiological processes such as hepatic glucose metabolism, long-term memory consolidation, and cellular survival (PubMed: 25901314). Dysregulation of the CREB/CRTC pathway is a hallmark of several diseases, including type 2 diabetes, where CRTC2 drives excessive gluconeogenesis, and various malignancies where CREB is overexpressed or CRTCs are involved in oncogenic fusions (PubMed: 15199141). Therapeutic interventions targeting this complex include small-molecule inhibitors like 666-15, which disrupts CREB-mediated transcription, and KG-501, which interferes with coactivator binding. Developing drugs for this target is challenging due to the ubiquitous nature of CREB signaling, which raises concerns about potential side effects on cognitive function and metabolic homeostasis.

Other names

CREB-CRTC complexCREB/CRTC signaling axisTORC (Transducer of Regulated CREB activity)CREB1CRTC1CRTC2CRTC3

Inhibition of CREB-mediated transcription, disruption of CREB-CRTC protein-protein interaction, and inhibition of CRTC nuclear translocation.