CRTC2

CRTC2 functions as a transcriptional coactivator of CREB that is negatively regulated by MARK2-dependent phosphorylation, which suppresses CREB-mediated transcription and mTOR activation in T cells; CD28 co-stimulatory signaling relieves this inhibition to enable CRTC2-driven transcriptional and metabolic programs [bio_10.1101_2025.10.13.682047]. Overexpression of CRTC2 in hippocampal neurons drives neuronal hyperactivity, linking CRTC2 activity levels to the regulation of neuronal excitability [bio_10.1101_2024.06.11.24308522].

1. 2024 Low

   Whether CRTC2 directly influences neuronal excitability was unknown; overexpression in hippocampal neurons revealed that elevated CRTC2 levels drive hyperactivity, establishing a functional connection between this CREB coactivator and neuronal firing.

   Evidence Multi-electrode array recordings and electrophysiology in hippocampal neurons overexpressing CRTC2 (preprint)

   PMID:bio_10.1101_2024.06.11.24308522

   Open questions at the time

   • Single functional readout (overexpression) without loss-of-function validation or pathway dissection
   • Downstream transcriptional targets mediating hyperactivity are not identified
   • Not independently replicated
2. 2025 Medium

   The upstream kinase controlling CRTC2 in T cells and the co-stimulatory signal that relieves CRTC2 inhibition were undefined; conditional knockout and phosphorylation assays showed MARK2 directly phosphorylates CRTC2 to suppress CREB transcription and mTORC1 activity, and CD28 engagement counteracts this inhibition.

   Evidence MARK2 conditional knockout mice, single-cell transcriptomics, in vitro phosphorylation assays, and functional rescue measuring CREB-dependent transcription and mTORC1 signaling (preprint)

   PMID:bio_10.1101_2025.10.13.682047

   Open questions at the time

   • Specific CRTC2 phosphorylation sites targeted by MARK2 and their individual functional contributions are not fully resolved
   • Mechanism by which CD28 signaling inhibits MARK2 activity toward CRTC2 is not defined
   • Whether other kinases (e.g., SIKs, AMPKs) contribute to CRTC2 regulation in T cells alongside MARK2 is not addressed

• How the MARK2-CRTC2-CREB axis integrates with other T cell signaling pathways beyond mTORC1, and whether the neuronal hyperactivity phenotype operates through the same CREB-dependent mechanism, remain open questions.
• No peer-reviewed, independently replicated studies define CRTC2 mechanism in either T cells or neurons
• Direct CRTC2 transcriptional target genes in T cells have not been comprehensively catalogued
• Structural basis for MARK2 recognition of CRTC2 is unknown