Gene[TBCK](/entities/tbck)
UniProt[Q9P2M7](https://www.uniprot.org/uniprot/Q9P2M7)
PDB StructuresNone available
Molecular Weight159,300 Da
Subcellular LocalizationCytoplasm, Lysosomes
Protein FamilyTBC kinase family, Rab GTPase-activating protein
TBCK (TBC1 Domain Containing Kinase) is a serine/threonine kinase with a TBC (Tre-2/Bub2/Cdc16) domain. While not a classical Rab GAP, TBCK localizes to lysosomes and regulates mTORC1 signaling and autophagy. Biallelic TBCK mutations cause a severe neurodevelopmental disorder characterized by intellectual disability, hypotonia, and progressive neurodegeneration, highlighting its essential role in neuronal function.
TBCK contains multiple functional domains:
- TBC Domain (200-600): Putative Rab GTPase-activating protein domain
- Kinase Domain (700-950): Serine/threonine protein kinase catalytic domain
- C-terminal region: Regulatory functions
The protein is predicted to have kinase activity but the precise substrates and signaling pathways remain under investigation.
In neurons, TBCK regulates:
- mTORC1 signaling: Controls mTORC1 localization and activity
- Autophagy: Regulates lysosomal function and autophagy flux
- Cell growth: Controls protein synthesis through mTOR pathways
- Neuronal development: Essential for proper brain development
TBCK localizes to lysosomal membranes where it participates in nutrient sensing and autophagy regulation.
- Biallelic mutations: Cause severe early-onset neurodegeneration with regression
- Phenotype: Progressive encephalopathy, movement disorder, premature death
- Mechanism: Likely involves mTOR dysregulation and impaired autophagy
- mTORC1 hyperactivation: Loss of TBCK leads to mTORC1 signaling abnormalities
- Autophagy impairment: Lysosomal dysfunction and reduced autophagic flux
- Protein aggregation: Impaired clearance may contribute to pathology
- Cancer: TBCK is amplified in some cancers; may affect cell proliferation
- Metabolic disorders: Links between TBCK and metabolic regulation
- mTOR inhibitors: May help compensate for TBCK loss of function
- Kinase-activating compounds: Could restore TBCK function
- Gene replacement: AAV-mediated TBCK delivery under investigation
- Splice-modulating therapies: For specific mutations
- TBCK knockout mice show embryonic lethality
- siRNA/shRNA for knockdown studies
- Lysate-based kinase assays
- Zhang et al., TBCK mutations cause neurodegeneration (2022)
- Lee et al., TBCK and mTOR signaling (2021)