cAMP response element-binding protein-CREB-binding protein-CREB-regulated transcription coactivator 2 transcriptional complex (CREB-CBP-CRTC2)

The cAMP response element-binding protein (CREB)-CREB-binding protein (CBP)-CREB-regulated transcription coactivator 2 (CRTC2) transcriptional complex is a fundamental regulatory unit in the control of cellular gene expression, particularly in response to hormonal and metabolic signals. This complex is central to hepatic gluconeogenesis, where CRTC2 acts as a metabolic sensor that translocates to the nucleus during fasting to facilitate the assembly of CREB and CBP on the promoters of key gluconeogenic enzymes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [1]. In pathological states such as Type 2 diabetes, the complex is often hyperactivated, leading to excessive glucose production and fasting hyperglycemia [2]. Beyond metabolism, the complex is implicated in various cancers where it drives the expression of genes promoting cell survival and proliferation [4]. Therapeutic strategies targeting this complex include small molecules that disrupt the protein-protein interactions between CREB and its coactivators or inhibitors of upstream kinases, such as salt-inducible kinases (SIKs), which regulate the phosphorylation and nuclear localization of CRTC2 [2, 3]. While promising for metabolic and oncogenic indications, targeting this complex presents significant challenges due to the ubiquitous role of CREB in essential processes like neuronal survival and memory formation [1].

Other names

CREB-CBP-TORC2 complexCREB/CBP/CRTC2 complexCRTC2-CREB-CBP complexCREB-CBP-CRTC2 complex

Disruption of the protein-protein interaction (PPI) between the KID domain of CREB and the KIX domain of CBP, or the inhibition of salt-inducible kinases (SIKs) to prevent CRTC2 dephosphorylation and nuclear translocation, thereby suppressing the transcription of gluconeogenic genes [1, 2, 3].