| 2014 |
BCKDK phosphorylates the E1α subunit of the branched-chain α-keto acid dehydrogenase complex (BCKD), inactivating it; loss-of-function mutations in BCKDK (p.L389P and p.R174Gfs1*) result in total loss of kinase activity, undetectable phospho-E1α, increased BCKD activity, and rapid BCAA catabolism, demonstrated in patient-derived fibroblasts. |
Functional analysis of missense and frameshift mutations in patient fibroblasts; measurement of kinase activity and phospho-E1α levels by western blot |
Human mutation |
High |
24449431
|
| 2017 |
BCKDK promotes colorectal cancer tumorigenesis through direct phosphorylation of MEK, activating the MAPK signaling pathway, independently of its role in BCAA catabolism; this was shown by co-immunoprecipitation and western blot in CRC cells, and inhibited by the BCKDK inhibitor phenyl butyrate. |
Co-immunoprecipitation, western blot, in vitro kinase assay, cell transformation assays, xenograft models |
EBioMedicine |
Medium |
28501528
|
| 2019 |
UBE3B (an E3 ubiquitin ligase mutated in Kaufman oculocerebrofacial syndrome) ubiquitinates BCKDK in vivo; BCKDK was identified as a substrate of UBE3B, linking UBE3B loss to perturbation of BCAA metabolic pathways and mitochondrial respiration. |
In vivo substrate identification (Ube3b knockout mice), Co-immunoprecipitation, metabolomics profiling of plasma and cortex |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
30808755
|
| 2020 |
Src kinase phosphorylates BCKDK at tyrosine 246 (Y246) in vitro and in cellulo; this phosphorylation enhances BCKDK kinase activity and protein stability, promoting CRC cell migration, invasion, and EMT. Knockdown/knockout of Src reduced BCKDK Y246 phosphorylation. |
In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (Y246 phospho-dead mutant), Src knockdown/knockout, phosphoproteomics |
Oncogene |
High |
32238881
|
| 2020 |
Aminopeptidase N (APN/CD13) mediates phosphorylation of BCKDK at serine 31 (S31); phosphorylated BCKDK then interacts with ERK1/2 and phosphorylates it, thereby activating the ERK signaling pathway in hepatocellular carcinoma cells. |
Phosphoproteomics, co-immunoprecipitation, proximity ligation assay, point mutation analysis, western blot, APN knockout in vitro and in vivo |
Cell death & disease |
Medium |
32457292
|
| 2021 |
BCKDK serves as a compensatory kinase for PDK1-4 (pyruvate dehydrogenase kinases) during embryonic development; in quadruple Pdk knockout embryos, PDC (pyruvate dehydrogenase complex) remained phosphorylated, and additional knockout of Bckdk eliminated PDC phosphorylation, increased PDC activity and pyruvate entry into the TCA cycle, and caused embryonic lethality. |
Sequential gene knockout (mouse models), PDC activity assay, phosphorylation status assessment by western blot |
Developmental cell |
High |
33773101
|
| 2021 |
BCKDK inhibition in triple-negative breast cancer reduces intracellular BCKAs, downregulates mitochondrial metabolism genes, reduces electron transport chain complex protein expression, oxygen consumption, and ATP production, and upregulates sestrin 2 while decreasing mTORC1 signaling and protein synthesis. |
Genetic silencing (siRNA/shRNA) and pharmacological inhibition of BCKDK, metabolite measurement, transcriptome analysis, mitochondrial respiration assays, mTORC1 signaling assessment |
Cell death discovery |
Medium |
34526485
|
| 2022 |
Loss-of-function mutation in BCKDK (p.Thr334del) causes hyperactivity of BCKDH and BCAA over-consumption, demonstrated by functional transfection assays in cells; BCKDK phosphorylation-mediated inactivation of BCKDH was thus directly shown to be the molecular mechanism of BCAA homeostasis in human disease. |
Cell transfection with mutant BCKDK construct, functional BCKDH activity assay, plasma and CSF metabolite measurement |
International journal of molecular sciences |
Medium |
35216372
|
| 2023 |
BCKDK inhibits TRIM21-mediated ubiquitination and degradation of talin1 in breast cancer; BCKDK interaction with talin1 was shown, and BCKDK prevented TRIM21-talin1 binding, thereby stabilizing talin1, activating the FAK/MAPK pathway, and promoting focal adhesion assembly and cell migration. |
Co-immunoprecipitation, western blot, loss-of-function (shRNA knockdown), in vitro migration assays, in vivo lung metastasis model |
Cell death & disease |
Medium |
37460470
|
| 2024 |
BCKDK phosphorylates BCAT1 at S5, S9, and T312, increasing its catalytic and antioxidant activity and stability; BCKDK also phosphorylates STUB1 (E3 ubiquitin ligase of BCAT1) at S19, disrupting STUB1-BCAT1 interaction and preventing BCAT1 ubiquitin-mediated degradation, thereby promoting GBM proliferation. |
In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, mass spectrometry, in vivo xenograft experiments |
Cancer letters |
High |
38621458
|
| 2024 |
BCKDK interacts with glucose-6-phosphate dehydrogenase (G6PD) and increases flux through the pentose phosphate pathway; forced G6PD expression rescued growth defects in BCKDK-deficient TNBC cells, placing BCKDK upstream of G6PD in metabolic reprogramming. |
Co-immunoprecipitation, mass spectrometry, isotope tracer studies, immunofluorescence, rescue (G6PD overexpression), cell viability assays |
Cell death & disease |
Medium |
39025830
|
| 2024 |
BCKDK interacts with the NDUFS1 subunit of mitochondrial Complex I to stabilize its function; loss of BCKDK disrupts this interaction, leading to Complex I destabilization, reduced membrane potential, increased ROS, and promotion of α-synuclein oligomerization and aggregation in dopaminergic neurons. |
Co-immunoprecipitation, mitochondrial membrane potential assay, ROS measurement, BCKDK knockdown/restoration in neuron-like cells and patient-derived iPS-derived dopaminergic neurons |
Acta neuropathologica communications |
Medium |
39709505
|
| 2024 |
BCKDK interacts with BCLAF1 and promotes its phosphorylation at serine 285; this modification enables BCLAF1 to bind the MYC promoter and enhance MYC transcription, which upregulates hexokinase 2 (HK2) to promote aerobic glycolysis and lung cancer progression and Trametinib resistance. |
Co-immunoprecipitation, western blot, chromatin immunoprecipitation, luciferase reporter assay, point mutation, RNA sequencing, cell-based functional assays |
Cell death and differentiation |
Medium |
40442441
|
| 2024 |
Nuclear-localized BCKDK phosphorylates RNF8 at Ser157, preventing ubiquitin-mediated degradation of RAD51, thereby facilitating homologous recombination repair (HRR) and promoting resistance to DNA damage-inducing therapy in breast cancer; this function is independent of BCKDK's metabolic role. |
Subcellular fractionation/localization (nuclear BCKDK), Co-IP, site-directed mutagenesis, RAD51 ubiquitination assay, HR repair functional assay, pharmacological inhibition |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
Medium |
40298908
|
| 2024 |
Fyn tyrosine kinase phosphorylates BCKDK at Y151, increasing its catalytic activity and protein stability, promoting GBM cell proliferation; elevated BCKDK also increases N-acetyl-L-alanine (NAAL) levels, which activates ERK signaling and promotes proliferation; silencing BCKDK increases ACY1 expression. |
In vitro and in vivo kinase assay, site-directed mutagenesis (Y151), metabolite profiling, western blot, tumor xenograft model |
Heliyon |
Medium |
39170503
|
| 2024 |
The BCKDK inhibitor BT2 acts as a mitochondrial uncoupler independently of its inhibitory effect on BCKDK; BT2 increases proton conductance across the mitochondrial inner membrane, lowering mitochondrial ROS production and de novo lipogenesis, as confirmed using patch-clamp electrophysiology and oxygen consumption measurements, and was active even in Bckdk-/- animals. |
Oxygen consumption measurement, mitochondrial membrane potential assay, patch-clamp electrophysiology, Bckdk knockout mouse model, de novo lipogenesis assay |
The Journal of biological chemistry |
High |
38301896
|
| 2024 |
PSMD14 deubiquitinase directly interacts with and deubiquitinates BCKDK, antagonizing TRIM21-mediated proteasomal degradation of BCKDK, thereby stabilizing BCKDK protein levels in GBM cells. |
Co-immunoprecipitation, deubiquitination assay, PSMD14 knockdown, western blot |
Cell death and differentiation |
Medium |
41876842
|
| 2024 |
BT2 (a BCKDK allosteric inhibitor) activates BCAA oxidation via inhibition of BCKDK, but also independently reduces plasma tryptophan by binding serum albumin and displacing tryptophan, releasing it for catabolism to kynurenine; this was demonstrated using Bckdk-/- mice (where BT2 could not activate BCAA oxidation but still depleted tryptophan), equilibrium dialysis, and albumin-deficient mice. |
Bckdk-/- mouse model, equilibrium dialysis, albumin-knockout mice, metabolite profiling |
bioRxivpreprint |
High |
38496495
|
| 2025 |
BT2 activates BCAA oxidation through BCKDK inhibition, but also independently reduces plasma tryptophan by binding serum albumin and displacing tryptophan; this off-target effect was confirmed in Bckdk-/- mice by equilibrium dialysis and albumin-deficient mice (peer-reviewed version of preprint 38496495). |
Bckdk-/- mouse model, equilibrium dialysis, albumin-knockout mice, plasma metabolite profiling |
Molecular metabolism |
High |
40348014
|
| 2025 |
In zebrafish, Bckdk acts as a post-translational regulator of the maternal-to-zygotic transition (MZT); Bckdk depletion reduces phosphorylation of Phf10/Baf45a (a BAF chromatin remodeling subunit), and expression of a phospho-mimetic Phf10 rescued epiboly defects and ZGA abnormalities caused by bckdk knockdown, placing BCKDK upstream of Phf10-mediated chromatin remodeling during MZT. |
CRISPR-RfxCas13d mRNA knockdown screen in zebrafish, phospho-proteomics, phf10 mRNA knockdown, phospho-mimetic Phf10 rescue, H3K27ac measurement |
The EMBO journal |
High |
41254269
|
| 2024 |
PRSS55 interacts with BCKDK and its substrate BCKDHA in mouse testes/sperm, as validated by co-immunoprecipitation and LC-MS/MS; loss of Prss55 results in accumulation of BCAAs in testes, suggesting PRSS55 modulates BCKDK-mediated BCAA catabolism in the context of sperm mitochondrial function. |
Co-immunoprecipitation, LC-MS/MS, Prss55-/- mouse model, metabolomics, mitochondrial function assays |
Cell & bioscience |
Medium |
41444608
|
| 2016 |
In BCKDK-deficient patient fibroblasts, loss of BCKDK increases superoxide anion production (2-fold), reduces ATP-linked respiration and intracellular ATP levels (to ~60%), and causes mitochondrial hyperfusion associated with changes in OPA1 and mitofusin 2/MFN2 forms; BCKDK knockdown in control fibroblasts recapitulated these mitochondrial phenotypes. |
Bioenergetics assays (oxygen consumption, ATP measurement), superoxide measurement, ultrastructural analysis (electron microscopy), western blot (OPA1, MFN2), siRNA knockdown |
Biochimica et biophysica acta |
Medium |
26809120
|
| 2024 |
In BCKDK-deficient mice, genetic re-regulation of BCAA catabolism via Dbt haploinsufficiency (reducing downstream catabolic flux) partially rescues biochemical and behavioral phenotypes, demonstrating that aberrant flux through the BCAA catabolic pathway (not just BCAA insufficiency) contributes to pathology. |
Mouse model of BCKDK deficiency, Dbt haploinsufficiency genetic epistasis, behavioral testing, plasma metabolite measurement |
Molecular genetics and metabolism reports |
Medium |
38770403
|
| 2025 |
In BCKDK-deficient mouse brains (but not skeletal muscle), fasting activates the integrated stress response (ISR) with upregulation of Atf4 and its targets including Slc7a5; stable isotope tracing showed lower BCAA-derived nitrogen delivery to brain glutamate in BCKDK KO mice, demonstrating a brain-specific metabolic vulnerability. |
Bckdk KO mouse model, stable isotope tracing with mass spectrometry imaging, protein synthesis measurement, ISR marker quantification (ATF4, target genes), mTORC1 signaling assessment |
The Journal of nutritional biochemistry |
Medium |
41587643
|