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Gene Review

PDK1  -  pyruvate dehydrogenase kinase, isozyme 1

Homo sapiens

Synonyms: PDH kinase 1, PDHK1, Pyruvate dehydrogenase kinase isoform 1
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Disease relevance of PDK1


High impact information on PDK1


Chemical compound and disease context of PDK1

  • Our findings show that PDK1 may be a superior alternative to Akt1 as a target for sensitizing breast cancer cells to chemotherapeutic agents, particularly gemcitabine [1].

Biological context of PDK1

  • Akt activation requires phosphorylation of Thr(308) and Ser(473) by 3-phosphoinositide-dependent kinase-1 and 2 (PDK1 and PDK2), respectively [11].
  • Mapping analysis revealed that this binding was only mediated by the catalytic domain of PDK1 and not by the pleckstrin homology domain [12].
  • Consistently, knockdown of the endogenous STRAP by the transfection of the small interfering RNA resulted in the decrease of PDK1 kinase activity [12].
  • Cells with high levels of phosphorylated PDK1 were more resistant to gemcitabine-induced apoptosis than cells expressing high levels of phosphorylated Akt1 [1].
  • We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) [13].

Anatomical context of PDK1


Associations of PDK1 with chemical compounds

  • However, the PDK1-overexpressing cells were more resistant to gemcitabine than were the Akt1-overexpressing cells [1].
  • Overexpression of PDK1 or Akt1 conferred similar resistance to treatment with paclitaxel or doxorubicin compared with control cells [1].
  • Secondly, thiamin pyrophosphate markedly decreases the amount of phosphate that PDK1 incorporates in sites 2 and 3 and that PDK2 incorporates in site 2 [17].
  • PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA [13].
  • The serine/threonine protein kinase phosphoinositide-dependent kinase 1 (PDK1) plays a central role in cellular signaling by phosphorylating members of the AGC family of kinases, including PKB/Akt [10].

Enzymatic interactions of PDK1

  • The identification of PDK1 as a kinase that phosphorylates the AGC family of kinases led to a hunt for 'PDK2', a hypothetical regulated kinase(s) that would be required for full activation of the AGC kinases [18].

Regulatory relationships of PDK1


Other interactions of PDK1

  • Taken together, these results suggested that STRAP acts as an intermediate signaling molecule linking between the phosphatidylinositol 3-kinase/PDK1 and the TGF-beta signaling pathways [12].
  • Regulation of transforming growth factor-beta signaling and PDK1 kinase activity by physical interaction between PDK1 and serine-threonine kinase receptor-associated protein [12].
  • Moreover, confocal microscopic study and immunostaining results demonstrated that PDK1 prevented the nuclear translocation of Smad3 in response to TGF-beta [12].
  • The signaling upstream of eNOS involving Akt and PDK1 were also suppressed by the HCMV infection [21].
  • Linking the active SHP2DeltaN to the PDK1 PH domain or the FRS2beta myristoylation sequence also induced Mek1 activation [22].

Analytical, diagnostic and therapeutic context of PDK1


  1. Differential roles of phosphoinositide-dependent protein kinase-1 and akt1 expression and phosphorylation in breast cancer cell resistance to Paclitaxel, Doxorubicin, and gemcitabine. Liang, K., Lu, Y., Li, X., Zeng, X., Glazer, R.I., Mills, G.B., Fan, Z. Mol. Pharmacol. (2006) [Pubmed]
  2. 3-phosphoinositide-dependent protein kinase-1 (PDK1) promotes invasion and activation of matrix metalloproteinases. Xie, Z., Yuan, H., Yin, Y., Zeng, X., Bai, R., Glazer, R.I. BMC Cancer (2006) [Pubmed]
  3. Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Majer, M., Popov, K.M., Harris, R.A., Bogardus, C., Prochazka, M. Mol. Genet. Metab. (1998) [Pubmed]
  4. Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Boulatnikov, I., Popov, K.M. Biochim. Biophys. Acta (2003) [Pubmed]
  5. Cytotoxicity of a non-cyclooxygenase-2 inhibitory derivative of celecoxib in non-small-cell lung cancer A549 cells. Tong, Z., Wu, X., Chen, C.S., Kehrer, J.P. Lung Cancer (2006) [Pubmed]
  6. PTEN and myotubularin: novel phosphoinositide phosphatases. Maehama, T., Taylor, G.S., Dixon, J.E. Annu. Rev. Biochem. (2001) [Pubmed]
  7. Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4. Nirula, A., Ho, M., Phee, H., Roose, J., Weiss, A. J. Exp. Med. (2006) [Pubmed]
  8. Phosphoinositide-dependent protein kinase 1, a sensor of protein conformation. Biondi, R.M. Trends Biochem. Sci. (2004) [Pubmed]
  9. PKCepsilon is a permissive link in integrin-dependent IFN-gamma signalling that facilitates JAK phosphorylation of STAT1. Ivaska, J., Bosca, L., Parker, P.J. Nat. Cell Biol. (2003) [Pubmed]
  10. Essential role of PDK1 in regulating endothelial cell migration. Primo, L., di Blasio, L., Roca, C., Droetto, S., Piva, R., Schaffhausen, B., Bussolino, F. J. Cell Biol. (2007) [Pubmed]
  11. p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils. Rane, M.J., Coxon, P.Y., Powell, D.W., Webster, R., Klein, J.B., Pierce, W., Ping, P., McLeish, K.R. J. Biol. Chem. (2001) [Pubmed]
  12. Regulation of transforming growth factor-beta signaling and PDK1 kinase activity by physical interaction between PDK1 and serine-threonine kinase receptor-associated protein. Seong, H.A., Jung, H., Choi, H.S., Kim, K.T., Ha, H. J. Biol. Chem. (2005) [Pubmed]
  13. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Kim, J.W., Tchernyshyov, I., Semenza, G.L., Dang, C.V. Cell metabolism. (2006) [Pubmed]
  14. Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with the induction of protein kinase Calpha. Zeng, X., Xu, H., Glazer, R.I. Cancer Res. (2002) [Pubmed]
  15. P2Y receptors activate MAPK/ERK through a pathway involving PI3K/PDK1/PKC-zeta in human vein endothelial cells. Montiel, M., de la Blanca, E.P., Jiménez, E. Cell. Physiol. Biochem. (2006) [Pubmed]
  16. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. Abbot, E.L., McCormack, J.G., Reynet, C., Hassall, D.G., Buchan, K.W., Yeaman, S.J. FEBS J. (2005) [Pubmed]
  17. Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Kolobova, E., Tuganova, A., Boulatnikov, I., Popov, K.M. Biochem. J. (2001) [Pubmed]
  18. Kinase phosphorylation: Keeping it all in the family. Peterson, R.T., Schreiber, S.L. Curr. Biol. (1999) [Pubmed]
  19. Retinoid-mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARalpha and RXR and involves the phosphoinositide 3-kinase and ERK-MAP kinase pathways. Hughes, P.J., Zhao, Y., Chandraratna, R.A., Brown, G. J. Cell. Biochem. (2006) [Pubmed]
  20. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. Seong, H.A., Jung, H., Kim, K.T., Ha, H. J. Biol. Chem. (2007) [Pubmed]
  21. Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Shen, Y.H., Zhang, L., Utama, B., Wang, J., Gan, Y., Wang, X., Wang, J., Chen, L., Vercellotti, G.M., Coselli, J.S., Mehta, J.L., Wang, X.L. Cardiovasc. Res. (2006) [Pubmed]
  22. Regulation of the mitogen-activated protein kinase signaling pathway by SHP2. Cunnick, J.M., Meng, S., Ren, Y., Desponts, C., Wang, H.G., Djeu, J.Y., Wu, J. J. Biol. Chem. (2002) [Pubmed]
  23. Survival-signaling pathway as a promising target for cancer chemotherapy. Fujita, N., Tsuruo, T. Cancer Chemother. Pharmacol. (2003) [Pubmed]
  24. 3'Phosphoinositide-dependent kinase-1 is essential for ischemic preconditioning of the myocardium. Budas, G.R., Sukhodub, A., Alessi, D.R., Jovanovi??, A. FASEB J. (2006) [Pubmed]
  25. Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. Engel, M., Hindie, V., Lopez-Garcia, L.A., Stroba, A., Schaeffer, F., Adrian, I., Imig, J., Idrissova, L., Nastainczyk, W., Zeuzem, S., Alzari, P.M., Hartmann, R.W., Piiper, A., Biondi, R.M. EMBO J. (2006) [Pubmed]
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