PRKG1
Overview
PRKG1 encodes cGMP-dependent protein kinase I (cGKI), including the cGKIβ isoform. In T-cell biology, cGKIβ acts as a negative regulator of TCR signaling by phosphorylating RHOA at S188, thereby attenuating downstream NFAT activation. In cutaneous T-cell lymphoma (CTCL), recurrent loss-of-function mutations in the leucine-zipper dimerization domain of PRKG1 destabilize cGKIβ homodimers, abolish RHOA phosphorylation, and enhance NFAT activation, representing a novel oncogenic mechanism via loss of TCR-signal antagonism.
Alterations observed in the corpus
- Leucine-zipper dimerization-domain mutations p.Glu17Lys and p.Arg21Gln in two Sézary syndrome cases; functionally loss-of-function alleles that destabilize cGKIβ homodimers, abolish 8-CPT-cGMP-driven RHOA S188 phosphorylation, and enhance NFAT activation — a novel oncogenic mechanism via loss of TCR-signal antagonism PMID:26551667
Cancer types (linked)
- Sézary Syndrome / CTCL: Recurrent LoF mutations in ~8% (2/25) of Sézary syndrome exomes; functionally validated as drivers of NFAT hyperactivation PMID:26551667
Co-occurrence and mutual exclusivity
- PRKG1 mutations converge with CARD11 linker-domain mutations and TNFRSF1B mutations on constitutive NFκB activation downstream of TCR signaling in CTCL PMID:26551667
Therapeutic relevance
- NFAT inhibition (FK506) had only modest antitumor effects in CTCL cell lines despite PRKG1-driven NFAT hyperactivation, suggesting combination strategies or alternative pathway nodes may be needed PMID:26551667
Open questions
- Functional consequences of PRKG1 LoF on chromatin and gene expression in CTCL have not been directly tested beyond the RHOA/NFAT axis PMID:26551667
Sources
This page was processed by entity-page-writer on 2026-05-14.