Disease relevance of PDK1

• 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].
• Mammary fat pad isografts of PDK1-expressing cells produced invasive adenocarcinomas [2].
• Recently, increased PDK activity has been implicated in the pathogenesis of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) in obese subjects [3].
• Here, we demonstrate that two members of the PDK family, PDK1 and PDK2, form heterodimeric species when coexpressed in the same Escherichia coli cell [4].
• The aim of the present studies was to investigate the potential of a celecoxib-derived PDK1 inhibitor (OSU03013), that does not inhibit cyclooxygenase-2, to kill lung cancer cells in vitro [5].

High impact information on PDK1

• This inositol lipid is an important regulator of cell growth and survival signaling through the Ser/Thr protein kinases PDK1 and Akt [6].
• Phosphorylation of the critical PKA threonine residue is stimulated by engagement of TCR/CD28 via a PDK1-dependent mechanism [7].
• PDK1 has the ability to recognize, interact with and phosphorylate specific substrate conformations and thus sets PDK1 at the centre of a protein conformation sensor mechanism [8].
• PKCepsilon function and the IFN-gamma response can be recovered by inhibition of PP2A if PDK1 is associated with PKCepsilon in this complex [9].
• We propose a model of spatial distribution of PDK1 and Akt in which the synthesis of phosphatidylinositol 3,4,5 triphosphate at plasma membrane by activation of phosphoinositide 3-kinase recruits both proteins at the leading edge of the polarized ECs and promotes cell chemotaxis [10].

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

• Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with the induction of protein kinase Calpha [14].
• 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].
• We also found that ATP stimulates both the phosphorylation of 3- phosphoinositide-dependent protein kinase-1 (PDK1) and its translocation to plasma membrane in a time-dependent manner [15].
• Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells [16].
• Essential role of PDK1 in regulating endothelial cell migration [10].

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

• Pharmacological inhibitors of the phosphatidylinositol 3-kinase, Akt, and PDK-1 also abrogated the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells [19].
• Coexpression of Smad proteins and wild-type PDK1 inhibits TGF-beta-induced transcription, as well as TGF-beta-mediated biological functions, such as apoptosis and cell growth arrest [20].

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

• 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 [23].
• Tissue microarray analysis of human breast cancers was used to measure PDK1 expression in invasive tumors by IHC [2].
• 3'Phosphoinositide-dependent kinase-1 (PDK1) is essential for ischemic preconditioning of the myocardium [24].
• The cardioprotective effect of PDK1 was not related to the effect that preconditioning has on sarcolemmal membrane action potential as revealed by di-8-ANEPPS, a sarcolemmal-potential sensitive dye, and laser confocal microscopy [24].
• The mechanism of action of these compounds was characterized by mutagenesis of PDK1, synthesis of compound analogs, interaction-displacement studies and isothermal titration calorimetry experiments [25].

References