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Literature summary for 2.7.11.2 extracted from

  • Hitosugi, T.; Fan, J.; Chung, T.W.; Lythgoe, K.; Wang, X.; Xie, J.; Ge, Q.; Gu, T.L.; Polakiewicz, R.D.; Roesel, J.L.; Chen, G.Z.; Boggon, T.J.; Lonial, S.; Fu, H.; Khuri, F.R.; Kang, S.; Chen, J.
    Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism (2011), Mol. Cell, 44, 864-877.
    View publication on PubMedView publication on EuropePMC

Activating Compound

Activating Compound Comment Organism Structure
additional information tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and pyruvate dehydrogenase complex binding Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
expression of GST-tagged PDHK1 in 293T cells, transient co-transfection with wild-type FGFR1 leads to tyrosine phosphorylation of PDHK1, but not in cells co-expressing a kinase dead form of FGFR1. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leading to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate, and expression in xenograft nude mice leads to reduced tumor growth Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information RNAi-mediated stable knockdown of endogenous human PDHK1 (hPDHK1) and rescue expression of wild-type and corresponding Y134F and Y239/240F mutant FLAG-tagged mouse PDHK1s to different extents, overview Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
additional information inhibition of FGFR1 by a small molecule inhibitor TKI258 results in decreased tyrosine phosphorylation levels of GST-PDHK1 and reduced PDHK1 activity Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrial matrix BCR-ABL, JAK2, and FLT3 are co-localized with PDHK1 Homo sapiens 5759
-

Organism

Organism UniProt Comment Textmining
Homo sapiens Q15118
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein tyrosine phosphorylation at Tyr243 of PDHK1 is required for enzyme activity and occurs in human cancers by diverse oncogenic tyrosine kinases, localized to different mitochondrial compartments, tyrosine phosphorylation by FGFR1 enhances PDHK1 activity by promoting ATP and pyruvate dehydrogenase complex binding. FGFR1 activates PDHK1 through direct phosphorylation at multiple tyrosine sites. Phosphorylation at both Y243 and Y244, but not Y136 may be required to promote ATP binding to PDHK1, while Y136 phosphorylation may only function to enhance binding between PDHK1 and pyruvate dehydrogenase complex Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
A-549 cell
-
Homo sapiens
-
carcinoma cell
-
Homo sapiens
-
H-1299 cell
-
Homo sapiens
-
K-562 cell
-
Homo sapiens
-
KG-1A cell
-
Homo sapiens
-
leukemia cell
-
Homo sapiens
-
MCF-7 cell
-
Homo sapiens
-
MO-91 cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + PDHA1
-
Homo sapiens ADP + phosphorylated PDHA1
-
?

Synonyms

Synonyms Comment Organism
PDK1 UniProt Homo sapiens
PDKH1
-
Homo sapiens
pyruvate dehydrogenase kinase 1
-
Homo sapiens

General Information

General Information Comment Organism
malfunction expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate, and reduced tumor growth in xenograft nude mice. Cells expressing catalytically less active mPDHK1 mutants, including Y134F and Y239/240F, rely more on oxidative phosphorylation for ATP production and cell proliferation compared to cells with mPDHK1 wild-type Homo sapiens
physiological function tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth in cancer cells. Oncogenic FGFR1 is localized in mitochondria in cancer cells, where it phosphorylates PDHK1 Homo sapiens