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

• These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis [7].
• Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass [7].
• Here we show that mice that lack PDK1 specifically in pancreatic beta cells (betaPdk1(-/-) mice) develop progressive hyperglycemia as a result of a loss of islet mass [7].
• The majority of identified phosphorylated sites lie in consensus sequences for the PDPK [8].
• PKB is activated by phosphorylation on residues threonine 308, by the protein kinase PDK1, and Serine 473, by a putative serine 473 kinase [9].

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

• A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1 [12].
• Interestingly, close to the PIF-pocket in PDK1, there is an ordered sulfate ion, interacting tightly with four surrounding side chains [13].
• Identification of tyrosine phosphorylation sites on 3-phosphoinositide-dependent protein kinase-1 and their role in regulating kinase activity [16].
• 3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in signal transduction pathways that activate phosphoinositide 3-kinase [16].
• Whereas PDK1-catalyzed phosphorylation and activation of PKB in vitro was highly dependent on the presence of phosphatidylinositol 3,4,5-trisphosphate (Ptdlns (3,4,5)P3), PDK1 catalyzed rapid phosphorylation and activation of p70 in vitro, independent of the presence of Ptdlns(3,4,5)P3 [20].
• Destabilization of PDK1 induced by geldanamycin (a Hsp90 inhibitor) was partially blocked in HEK 293 cells expressing PDK1-Y9F [21].

Physical interactions of PDPK1

• There is a 3-phosphoinositide-dependent protein kinase 1 (PDK1) interacting fragment (PIF) in the tail of NHERF2 [22].
• Interaction of these two proteins is constitutive and mediated by a PDK-1 binding motif on Grb14 [23].

Enzymatic interactions of PDPK1

• 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro [20].
• However, PTS-tagged CISK with deleted PX domain was able to direct 3-phosphoinositide-dependent protein kinase-1 (PDK-1) into the peroxisomes [24].
• In addition to a direct interaction, PDK1 also phosphorylated Thr(774) in the activation loop and activated PKN [25].

Regulatory relationships of PDPK1

• Disruption of this motif by point mutation or deletion of the Grb14 SH2 domain prevents the insulin-triggered membrane translocation of PDK-1 [23].
• PDK-1-induced activation of a C-terminal truncation mutant of p70S6K was also enhanced by myr-PKCzeta [26].
• 3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation [27].
• SLD also blocked the EGF-stimulated membrane translocation of 3-phosphoinositide-dependent protein kinase 1 and inhibited phosphatidylinositol 3-kinase activity [28].

Other interactions of PDPK1

• Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase [29].
• Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown [30].
• The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1 [22].
• Thus, Grb14 serves as an adaptor protein to recruit PDK-1 to activated insulin receptor, thus promoting Akt phosphorylation and transduction of the insulin signal [23].
• From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors [2].

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].

References