Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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3-phosphoinositide dependent protein kinase 1(PDPK1) 3-phosphoinositide dependent protein kinase 1(PDPK1) Related Genes Homo sapiens
CHROMOSOME 16,
CYTOBAND 16p13.3,
ENSEMBL_GENE_ID ENSG00000140992,
GENERIF_SUMMARY PDPK1 activity is regulated by reversible phosphorylation, possibly by a member of the Src kinase family., association of PDK1 with Hsp90 regulates its stability, solubility, and signaling, Substitution of the autophosphorylation site Thr516 with a negatively charged residue confers constitutive activity to mouse 3-phosphoinositide-dependent protein kinase-1 in cells, Data show that the translocation of 3-phosphoinositide-dependent protein kinase-1 from cytosol to the plasma membrane is critical for Akt and glycogen synthase kinase-3 activation., A point mutation in the substrate-binding region of PDK1 (L155E) rendered PDK1 incapable of phosphorylating PKB., 2.0 A crystal structure of the PDK1 kinase domain in complex with ATP, 14-3-3 protein binds to PDK1 at Ser241 and negatively regulates PDK1 kinase activity., PDK1 kinase activity is negatively regulated by binding to 14-3-3, In some growth factor-activated AGC protein kinases, phosphorylation of the hydrophobic motif creates a specific docking site that recruits and activates PDK1, which then phosphorylates the activation loop., PDK1 has a role in activating atypical PKC and regulating the degradation of p21(WAF1), The in vivo role of the PIF-binding site of PDK1 is defined by knock-in mutation., peroxisomal targeting signal (PTS)-tagged CISK with deleted PX domain was able to direct 3-phosphoinositide-dependent protein kinase-1 (PDK-1) into peroxisomes, Src- & ROS-dependent PDK1 activation leads to site-specific PAK1 phosphorylation. This is critically important for PDGF-induced VSMC migration, a process integral to the vascular response to injury that leads to vessel occlusion & plaque formation., role in metabolic actions of insulin, the integrity of the alpha C-helix and HM-pocket in PDK1 is not regulated by T-loop phosphorylation, PDK1 undergoes rapid and transient phosphorylation on S396, which was dependent upon plasma membrane localization; phosphorylation of S396 is necessary for nuclear shuttling of PDK1., PDK1 plays a critical role by nucleating the TCR-induced NF-kappaB activation pathway in T cells, results indicate that 3-phosphoinositide-dependent protein kinase-1 is a critical regulator of cell survival by modulating the IkappaB kinase (IKK)/nuclear factor-kappaB pathway, STRAP acts as an intermediate signaling molecule linking between the phosphatidylinositol 3-kinase/PDK1 and the TGF-beta signaling pathways, PDK-1 may promote oncogenesis in part through the activation of AKT and p7, PDK1 mediates mammary epithelial cell growth and invasion in part by MT1-MMP induction, which in turn activates MMP-2 and modulates the ECM proteins decorin and collagen, PDK1-catalyzed trans-phosphorylation of PDK1-Tide approximates a Rapid Equilibrium Random Bi Bi system, where motions in the central ternary complex are largely rate-determining, These data reveals for the first time that PDK1 and PKB may differentially activate NF-kappaB, and that TPCK may subserve a useful anti-inflammatory function by inhibiting IKKbeta., Ras is able to promote monocyte lineage selection via PKC and PDK1., PDK1 negatively regulates TGF-beta-mediated signaling in a PDK1 kinase-dependent manner via a direct physical interaction with Smad proteins, and Smad proteins can act as potential positive regulators of PDK1, Loss of PTEN expression in Jurkat T cells does not impact on the PDK-1/PKC pathway and that only a subset of kinases, such as PKB/Akt, are perturbed as a consequence PTEN loss., PDK-1/AKT pathway is activated in RMS and may play an important role in survival of RMS(rhabdomyosarcoma). PDK-1/AKT pathway may be an attractive therapeutic target for cancer intervention in RMS using OSU-03012., 3-Hydroxyanthranilic acid inhibits NF-kappaB activation upon T cell antigen receptor engagement by specifically targeting PDK1, These data suggest that phosphorylation of PDK1 on Tyr(9), distinct from Tyr(373/376), is important for PDK1/Src complex formation, leading to PDK1 activation., There is a non-catalytic role for PDK1 in regulating cortical acto-myosin and cell motility., 7-ketocholesterol-induced apoptosis has a role in phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway, p21(Ras)-mediated survival signaling is regulated by via a PI(3)K-AKT pathway, which is dependent upon both PDK1 and PKCdelta, and PDK1 activates and regulates PKCdelta to determine the fate of cells containing a mutated, activated p21(Ras)., Our findings suggest that IGF-I may regulate neuronal PDK-1 differently than in non-neuronal cells, which may indicate a novel role for PDK-1 in IGF-I-mediated neuroprotective signaling., The SHP-1, The identification of c-Jun as a transcriptional regulator of PDK1 expression highlights key mechanisms underlying c-Jun oncogenic activity, and provides new insight into the nature of up-regulated Akt and PKC in melanoma., results provide evidence that PDK1 and ASK1 directly interact and phosphorylate each other and act as negative regulators of their respective kinases in resting cells, disruption of phosphoinositide-dependent kinase-1 interaction with IGF-1R reduces IGF-1 survival effects in cancer cells, Data show that AKT1 and AKT2 appeared to regulate growth through FOXO proteins, but not through either GSK3beta or mTOR, and in contrast, inactivation of PDPK1 affected GSK3beta and mTOR activation., We evaluated the presence of mutations in PIK3CA, AKT1, AKT2, AKT3, PTEN, and PDPK1 genes in 83 papillary thyroid carcinomas, These studies show that PDK1 plays a pivotal role in MAPK and PI3K signaling in tumor cells., PDK1 with AKT1 is sufficient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase, analysis of PDK1 kinase inhibitors with a novel mechanism of action, Findings reveal a novel mechanism for recruitment of PDK1 to the SHPS-1 signaling complex, which is required for IGF-I-stimulated AKT Thr(308) phosphorylation and inhibition of apoptosis., Regulation of 3-phosphoinositide-dependent protein kinase 1 activity by homodimerization in live cells., PDK1 signaling network takes part in regulating cardiac viability and function in mice, and may be also involved in human heart failure disease., Association with colon and rectal cancer, a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems., Findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling., Data suggest that glioma cell survival occurs through a PI(3)-kinase/PDK1/PKC-iota/BAD mediated pathway., miR-375 is frequently down-regulated in esophageal cancer and is a negative regulator of PDK1, The role of PDK1 in cancer and approaches used to inhibit PDK1 were studied., The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy., Silencing PDK1 significantly inhibited cell proliferation and invasion, and promoted cell apoptosis in esophageal cancer EC9706 cells., IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation., Protein phosphatase 2A (PP2A)-specific ubiquitin ligase MID1 is a sequence-dependent regulator of translation efficiency controlling 3-phosphoinositide-dependent protein kinase-1 (PDPK-1)., identifed the Ubiquitin-Specific Protease 4 (USP4) as an enzyme that removes ubiquitin from PDK1 in vivo and in vitro and co-localizes with PDK1 at the plasma membrane when the two proteins are overexpressed, indicating direct deubiquitination, PDK1 in apical signaling endosomes participates in the rescue of the polarity complex atypical PKC by intermediate filaments in intestinal epithelia., PDK1 and PLCgamma1 act on the same signalling cascade, and the PDK1/PLCgamma1 pathway is required for regulation of cell invasion., these findings suggest that Hsp90 plays a critical role in the regulation of HCV RNA polymerase phosphorylation via the PDK1-PRK2 signaling pathway., Lower phosphorylation levels of PDK1 is associated with poor treatment response in rectal cancer., LOX-1 up-regulation induced by AGE-BSA was a receptor mediated through RAGE and is via the PI3K/PDK1/mTORC2 pathway, results suggest that PDK1 may contribute to breast cancer, even in the absence of phosphatidylinositol 3 kinase oncogenic mutations and through both Akt-dependent and Akt-independent mechanisms, High 3-phosphoinositide-dependent protein kinase 1 is associated with esophageal cancer., cytoplasmic localization of PDK1 correlated only with early-stage, low-risk tumors, whereas nuclear PDK1 localization correlated with high-risk tumors, cell-autonomous phosphoinositide 3-kinase and 3-phosphoinositide-dependent protein kinase 1 are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia, and pancreatic ductal adenocarcinoma formation, PTD-PDK1- Thr(513)-Asp selectively inhibited binding between PDK1 and CARMA1., Upregulation of PKCeta contributes to breast cancer cell growth and targeting either PKCepsilon or PDK1 triggers PKCeta downregulation, findings show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival; PDK1-PLK1-MYC signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell self-renewal, Data propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell., The crystal structural analysis of PDK1 located the PIF-pocket as the catalytic domain and for substrate recognition., these data show that overexpression of PDK1 is common in acute myelomonocytic leukemia and is associated with poorer treatment outcome, probably arising from the cytoprotective function of PDK1., miR-375 negatively regulates the expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) by directly targeting the 3'UTR of the PDK1 transcript, throught Akt signaling pathway., phosphorylating the T-loop Akt residue Thr(308) by PDK1 requires Raptor of the mTORC1 complex as a platform or scaffold protein., PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway, suggesting that PDK1 plays a specific and distinct role from the canonical PIK3/Akt pathway and promotes oncogenesis independently of AKT., Combined inhibition of PDK1 and CHK1 represents a potentially effective therapeutic approach to reduce the growth of human glioblastoma., our results demonstrate that ciglitazone inhibits PDK1 expression through AMPKalpha-mediated induction of Egr-1 and Egr-1 binding to the specific DNA site in the PDK1 gene promoter, which is independent of PPARgamma, Studied miR-138 and PDK1 mRNA expression in serum of NSCLC patients and their associations with patients' prognosis., A functional pathway involving PDK1-mediated activation of MRCKA, links EGF signaling to myosin contraction and directional migration., Data suggest that regulation of activity of PDK1 (including PDK1 in neoplastic cells) involves serine/threonine/tyrosine phosphorylation, subcellular localization, regulator binding, homodimerization, and conformation changes. [REVIEW], Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles., C4-CER can replace the PI3K/mTORC2 pathway to directly induce SGK1 to autophosphorylate at Ser422, an initial step leading to activation of PDK1 and of SGK1 by PDK1., Upregulation of PDK1 protein associates with aggressive progression and poor prognosis in esophageal squamous cell carcinoma patients., This work provides a promising new scaffold for the development of high-affinity PIF pocket ligands, which may be used to enhance the anticancer activity of existing PDK1 inhibitors., modulation of integrin endocytosis by PDK1 hampers endothelial cell adhesion and migration on extracellular matrix, thus unveiling a novel role for this kinase., Data illustrate a critical role for PDK1 in transducing inhibitory signals on eosinophil effector function. Stimulation of EP4 receptors caused PDK1 phosphorylation at Ser396 and induced PI3K-dependent nuclear translocation of PDK1., SGK3 is a key mediator of PDK1 activity in melanoma., data show that PDK1 played a pivotal role in the growth of angiosarcoma cells., Decreased PDK1 level is closely associated with reduced Akt/cyclin D1 activity., MiR-138 regulation of PI3K signaling in ASMCs by altering the expression of PDK1., Altogether, these findings indicate the possibility to rationally target PDK1 in human tumors in order to counteract cancer cell dissemination in the organism., Data show that NSC156529 inhibits the interaction of endogenous serine/threonine kinase AKT (AKT1) and 3-phosphoinositide dependent protein kinase-1 (PDPK1) proteins., PDK1 functions as a tumor promoter in human gallbladder cancer by upregulating JunB, promoting epithelial mesenchymal transformation, and cell migration., DK1 inhibits the formation of the TAK1-TAB2-TRAF6 complex and leads to the inhibition of TRAF6 ubiquitination., Dephosphorylation of PDK-1 and the resulting changes to Akt phosphorylation is one of the mechanisms by which infection with Helicobacter pylori alter the balance between apoptosis and cell proliferation., Low PDK1 expression is associated with Ovarian Serous Carcinoma., AMIGO2 is an important regulator of the PDK1-Akt pathway., PGE2 increases normal bronchial epithelial cell proliferation through increased PDK1 gene expression that is dependent on EP4 and induction of c-Jun., Data suggest that claudin-18 suppresses the abnormal proliferation and motility of lung epithelial cells mediated by inhibition of phosphorylation of phosphoinositide-dependent protein kinase-1 and proto-oncogene protein c-akt (Akt).,
OFFICIAL_GENE_SYMBOL PDPK1,
SP_COMMENT catalytic activity:ATP + a protein = ADP + a phosphoprotein., function:Phosphorylates and activates not only PKB/AKT, but also PKA, PKC-zeta, RPS6KA1 and RPS6KB1. May play a general role in signaling processes and in development (By similarity). Isoform 3 is catalytically inactive., PTM:Phosphorylated on tyrosine and serine/threonine. Phosphorylation on Ser-241 in the activation loop is required for full activity. PDK1 itself can autophosphorylate Ser-241, leading to its own activation., similarity:Belongs to the protein kinase superfamily., similarity:Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDK1 subfamily., similarity:Contains 1 PH domain., similarity:Contains 1 protein kinase domain., subcellular location:Membrane-associated after cell stimulation leading to its translocation. Tyrosine phosphorylation seems to occur only at the plasma membrane., subunit:Interacts with TUSC4., tissue specificity:Appears to be expressed ubiquitously.,