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Gene Review

PDPK1  -  3-phosphoinositide dependent protein kinase 1

Homo sapiens

Synonyms: 3-phosphoinositide-dependent protein kinase 1, PDK1, PDPK2, PDPK2P, PRO0461, ...
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Disease relevance of PDPK1

  • To further validate this observation, we used small interfering RNA oligonucleotides to selectively knock down PDK1 or Akt1 expression in MCF7 human breast cancer cells [1].
  • Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells [2].
  • Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line [3].
  • We cloned a full-length pdk-1 cDNA from a human brain cDNA library, and the adenovirus to overexpress wild type PDK-1 (PDK-1WT) or membrane-targeted PDK-1 (PDK-1CAAX) was constructed [4].
  • We used antisense oligonucleotides directed against PDK-1 expression to explore the role of PDK-1 in human glioblastoma cells (U87-MG), which express a mutant PTEN allele [5].

Psychiatry related information on PDPK1

  • Music-exposed mice completed a maze learning task with fewer errors than the white noise-exposed mice and had lower levels of BDNF and higher levels of TrkB and PDK1 in the cortex [6].

High impact information on PDPK1


Chemical compound and disease context of PDPK1

  • 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].
  • These effects of H(2)O(2) and vanadate were found in 293T cells and CH310T1/2 cells expressing exogenous PDK1 and in A20 lymphoma cells expressing endogenous PDK1 [10].
  • Site-specific analysis of tyrosine hydroxylase phosphorylation in rat pheochromocytoma led previously to the identification of a novel growth factor-sensitive serine/threonine protein kinase, designated proline-directed protein kinase (PDPK) [11].

Biological context of PDPK1

  • A RSK2-S386K mutant showed no interaction with PDK1 or phosphorylation at Ser227 [12].
  • High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site [13].
  • Our study extend recent findings which implicate PDK1 in the activation of protein kinases B and C and p70(S6K), suggesting that PDK1 controls several major growth factor-activated signal transduction pathways [14].
  • The siRNA-mediated PDK1 gene silencing attenuated NF-kappaB activity and increased TRAIL-mediated cytotoxicity [15].
  • Cells with high levels of phosphorylated PDK1 were more resistant to gemcitabine-induced apoptosis than cells expressing high levels of phosphorylated Akt1 [1].

Anatomical context of PDPK1

  • The activity of PDK1 localized to the plasma membrane was also increased by insulin treatment [16].
  • In addition, activation of PDK1 is sufficient to phosphorylate PKB at Thr(308) in the cytosol [17].
  • Our findings provide convincing evidence that aPKCs and upstream activators, PI 3-kinase and PDK-1, play important roles in insulin-stimulated glucose transport in preadipocyte-derived human adipocytes [18].
  • We next correlated the expression and activation-specific phosphorylation of PDK1 and Akt1 with the cytotoxic effects of the same agents in several human breast cancer cell lines [1].
  • In addition to the decreased translation of many RNAs, a smaller number of RNAs show increased association with polyribosomes in PDK-1-/- ES cells relative to PDK-1+/+ ES cells [19].

Associations of PDPK1 with chemical compounds


Physical interactions of PDPK1


Enzymatic interactions of PDPK1


Regulatory relationships of PDPK1


Other interactions of PDPK1


Analytical, diagnostic and therapeutic context of PDPK1

  • The roles of these residues were investigated through a combination of site-directed mutagenesis and kinetic studies, the results of which confirm that this region of PDK1 represents a phosphate-dependent docking site [13].
  • We identify which mRNAs are most dramatically translationally regulated in cells lacking PDK-1 expression by performing microarray analysis of total and polysomal RNA in these cells [19].
  • Co-immunoprecipitation studies reveal that PDK-1 associates preferentially with its substrate, unphosphorylated protein kinase C, by a direct mechanism [31].
  • UCN-01 directly suppressed upstream AKT kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) (IC(50) <33 nM) both in vitro and in tumor xenografts [32].
  • It is concluded that PDK-1, whose structure has been determined by X-ray crystallography, and its mutants, may serve as particularly useful surrogates for the study of PKC inhibitors [33].


  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. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Zhu, J., Huang, J.W., Tseng, P.H., Yang, Y.T., Fowble, J., Shiau, C.W., Shaw, Y.J., Kulp, S.K., Chen, C.S. Cancer Res. (2004) [Pubmed]
  3. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. Arico, S., Pattingre, S., Bauvy, C., Gane, P., Barbat, A., Codogno, P., Ogier-Denis, E. J. Biol. Chem. (2002) [Pubmed]
  4. Membrane localization of 3-phosphoinositide-dependent protein kinase-1 stimulates activities of Akt and atypical protein kinase C but does not stimulate glucose transport and glycogen synthesis in 3T3-L1 adipocytes. Egawa, K., Maegawa, H., Shi, K., Nakamura, T., Obata, T., Yoshizaki, T., Morino, K., Shimizu, S., Nishio, Y., Suzuki, E., Kashiwagi, A. J. Biol. Chem. (2002) [Pubmed]
  5. Inhibition of PDK-1 activity causes a reduction in cell proliferation and survival. Flynn, P., Wongdagger, M., Zavar, M., Dean, N.M., Stokoe, D. Curr. Biol. (2000) [Pubmed]
  6. Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults. Chikahisa, S., Sei, H., Morishima, M., Sano, A., Kitaoka, K., Nakaya, Y., Morita, Y. Behav. Brain Res. (2006) [Pubmed]
  7. Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. Hashimoto, N., Kido, Y., Uchida, T., Asahara, S., Shigeyama, Y., Matsuda, T., Takeda, A., Tsuchihashi, D., Nishizawa, A., Ogawa, W., Fujimoto, Y., Okamura, H., Arden, K.C., Herrera, P.L., Noda, T., Kasuga, M. Nat. Genet. (2006) [Pubmed]
  8. Phosphorylation of steroid hormone receptors. Ortí, E., Bodwell, J.E., Munck, A. Endocr. Rev. (1992) [Pubmed]
  9. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Maira, S.M., Galetic, I., Brazil, D.P., Kaech, S., Ingley, E., Thelen, M., Hemmings, B.A. Science (2001) [Pubmed]
  10. Oxidative stress and vanadate induce tyrosine phosphorylation of phosphoinositide-dependent kinase 1 (PDK1). Prasad, N., Topping, R.S., Zhou, D., Decker, S.J. Biochemistry (2000) [Pubmed]
  11. Characterization of the cytoplasmic proline-directed protein kinase in proliferative cells and tissues as a heterodimer comprised of p34cdc2 and p58cyclin A. Hall, F.L., Braun, R.K., Mihara, K., Fung, Y.K., Berndt, N., Carbonaro-Hall, D.A., Vulliet, P.R. J. Biol. Chem. (1991) [Pubmed]
  12. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. Frödin, M., Jensen, C.J., Merienne, K., Gammeltoft, S. EMBO J. (2000) [Pubmed]
  13. High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site. Biondi, R.M., Komander, D., Thomas, C.C., Lizcano, J.M., Deak, M., Alessi, D.R., van Aalten, D.M. EMBO J. (2002) [Pubmed]
  14. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. Jensen, C.J., Buch, M.B., Krag, T.O., Hemmings, B.A., Gammeltoft, S., Frödin, M. J. Biol. Chem. (1999) [Pubmed]
  15. 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. Tanaka, H., Fujita, N., Tsuruo, T. J. Biol. Chem. (2005) [Pubmed]
  16. Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity. Park, J., Hill, M.M., Hess, D., Brazil, D.P., Hofsteenge, J., Hemmings, B.A. J. Biol. Chem. (2001) [Pubmed]
  17. Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. Wick, M.J., Dong, L.Q., Riojas, R.A., Ramos, F.J., Liu, F. J. Biol. Chem. (2000) [Pubmed]
  18. PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes. Bandyopadhyay, G., Sajan, M.P., Kanoh, Y., Standaert, M.L., Quon, M.J., Lea-Currie, R., Sen, A., Farese, R.V. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  19. Translational deregulation in PDK-1-/- embryonic stem cells. Tominaga, Y., Tamgüney, T., Kolesnichenko, M., Bilanges, B., Stokoe, D. Mol. Cell. Biol. (2005) [Pubmed]
  20. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Alessi, D.R., Kozlowski, M.T., Weng, Q.P., Morrice, N., Avruch, J. Curr. Biol. (1998) [Pubmed]
  21. Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. Yang, K.J., Shin, S., Piao, L., Shin, E., Li, Y., Park, K.A., Byun, H.S., Won, M., Hong, J., Kweon, G.R., Hur, G.M., Seok, J.H., Chun, T., Brazil, D.P., Hemmings, B.A., Park, J. J. Biol. Chem. (2008) [Pubmed]
  22. The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1. Chun, J., Kwon, T., Lee, E., Suh, P.G., Choi, E.J., Sun Kang, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  23. The adaptor protein Grb14 regulates the localization of 3-phosphoinositide-dependent kinase-1. King, C.C., Newton, A.C. J. Biol. Chem. (2004) [Pubmed]
  24. Peroxisomal targeting as a tool for assaying potein-protein interactions in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1 in vivo in a phosphorylation-dependent manner. Nilsen, T., Slagsvold, T., Skjerpen, C.S., Brech, A., Stenmark, H., Olsnes, S. J. Biol. Chem. (2004) [Pubmed]
  25. Phosphorylation of protein kinase N by phosphoinositide-dependent protein kinase-1 mediates insulin signals to the actin cytoskeleton. Dong, L.Q., Landa, L.R., Wick, M.J., Zhu, L., Mukai, H., Ono, Y., Liu, F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  26. p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex. Romanelli, A., Martin, K.A., Toker, A., Blenis, J. Mol. Cell. Biol. (1999) [Pubmed]
  27. 3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation. Yin, Y., Yuan, H., Wang, C., Pattabiraman, N., Rao, M., Pestell, R.G., Glazer, R.I. Mol. Endocrinol. (2006) [Pubmed]
  28. Scalaradial inhibition of epidermal growth factor receptor-mediated Akt phosphorylation is independent of secretory phospholipase A2. Xie, Y., Liu, L., Huang, X., Guo, Y., Lou, L. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  29. Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase. Andjelković, M., Maira, S.M., Cron, P., Parker, P.J., Hemmings, B.A. Mol. Cell. Biol. (1999) [Pubmed]
  30. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Balendran, A., Casamayor, A., Deak, M., Paterson, A., Gaffney, P., Currie, R., Downes, C.P., Alessi, D.R. Curr. Biol. (1999) [Pubmed]
  31. The carboxyl terminus of protein kinase c provides a switch to regulate its interaction with the phosphoinositide-dependent kinase, PDK-1. Gao, T., Toker, A., Newton, A.C. J. Biol. Chem. (2001) [Pubmed]
  32. Survival-signaling pathway as a promising target for cancer chemotherapy. Fujita, N., Tsuruo, T. Cancer Chemother. Pharmacol. (2003) [Pubmed]
  33. Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides. Bartlett, S., Beddard, G.S., Jackson, R.M., Kayser, V., Kilner, C., Leach, A., Nelson, A., Oledzki, P.R., Parker, P., Reid, G.D., Warriner, S.L. J. Am. Chem. Soc. (2005) [Pubmed]
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