PRKAG2
Overview
PRKAG2 (Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2) encodes a regulatory gamma subunit of AMP-activated protein kinase (AMPK). In chromophobe renal cell carcinoma (chRCC), it harbors predicted-activating mutations in the CBS pseudosubstrate (CBS2) and AMP-binding (CBS4) domains, and is strongly overexpressed versus papillary RCC, nominating AMPK dysregulation as a chRCC metabolic driver.
Alterations observed in the corpus
- p.Ile388Val (pseudosubstrate CBS2) and p.Arg531Gln (CBS4, AMP-binding) substitutions in chRCC; predicted activating by analogy to glycogen storage cardiomyopathy mutants; strongly upregulated in chRCC/oncocytoma vs pRCC (~3.4 log fold; P < 5 × 10⁻⁹⁰) PMID:25401301
Cancer types (linked)
- chRCC: CBS-domain activating mutations and marked overexpression define a metabolically dysregulated subtype; analogous PRKAG1 p.Arg299Gln found in independent validation cohort PMID:25401301
Co-occurrence and mutual exclusivity
- Co-occurs with PDHB mutations in a chRCC subtype with combined metabolic deregulation PMID:25401301
Therapeutic relevance
- Combined PRKAG2 + PDHB mutation defines a chRCC subtype potentially actionable via AMPK or PDH modulators; mTORC1 pathway also implicated in the same tumors via TSC1/TSC2/MTOR mutations; no clinical trial data available PMID:25401301
Open questions
- Functional consequence of individual PRKAG2 CBS-domain substitutions in renal cancer cells has not been directly validated; therapeutic benefit of AMPK modulation in PRKAG2-mutant chRCC is hypothetical PMID:25401301
Sources
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