Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression

Area of Science:

• Molecular Biology
• Cell Signaling
• Gene Regulation

Background:

• Hormones and growth factors stimulate gene expression via phosphorylated CREB (P-CREB) and its association with CBP/p300.
• Stress signals induce P-CREB but have minimal impact on CRE-dependent transcription, unlike cAMP signaling.

Purpose of the Study:

• To elucidate the role of the coactivator TORC2 in mediating differential gene expression responses to cAMP and stress pathways.
• To understand why P-CREB fails to activate transcription under stress despite comparable phosphorylation levels.

Main Methods:

• Investigated the association of TORC2 with CBP/p300 in response to cAMP and stress.
• Analyzed the recruitment of CBP/p300 to CREB target genes under different signaling conditions.
• Utilized a gain-of-function mutant CREB to assess the impact on transcription.

Main Results:

• TORC2 mediates cAMP-induced gene activation by associating with CBP/p300 and enhancing its recruitment to CREB target genes.
• TORC2 is not activated by stress signals, leading to a block in CBP/p300 recruitment and impaired CRE-dependent transcription.
• A mutant CREB with higher CBP affinity rescued transcription in stress-exposed cells, highlighting TORC2's pivotal role.

Conclusions:

• TORC2 acts as a crucial coactivator, differentiating the transcriptional outcomes of cAMP and stress signaling pathways on CREB.
• The recruitment of CBP/p300, facilitated by TORC2, is a key regulatory step in CREB-mediated gene expression.
• These findings identify TORC2 as a long-sought cofactor explaining differential CREB pathway activation.