Affinage

PDK1

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial · UniProt Q15118

Audit flag: wrong gene
Length
436 aa
Mass
49.2 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDK1 (PDPK1) is a master AGC-family serine/threonine kinase that sits at the hub of PI3K-dependent signaling, transducing lipid second-messenger cues into activation of downstream effector kinases that control cell growth, motility, and differentiation (PMID:9368760, PMID:9247112). It comprises a catalytic domain and a C-terminal pleckstrin homology (PH) domain, and phosphorylates the activation loop of its substrates: PKB/Akt at Thr308 (in a manner requiring PtdIns(3,4,5)P3/PtdIns(3,4)P2 binding by the substrate's own PH domain) (PMID:9368760), p70S6K at Thr229 (PMID:9445476), and PKC isoforms with which it forms complexes (PMID:9748166, PMID:9768361). PDK1 uses two distinct substrate-engagement strategies: PIP3-dependent co-localization at the membrane for Akt, versus a PIF/HM-pocket docking interaction that is required for activation of all other substrates but dispensable for Akt (PMID:18802401, PMID:17110931). Autoactivation proceeds through PIP3-driven face-to-face dimerization and trans-autophosphorylation, with the PH domain providing autoinhibition relieved by cooperative PIP3 binding (PMID:35387990). Its output is tuned by multiple regulatory layers: an mTORC1→S6K1 negative feedback loop in which S6K1 phosphorylates the PDK1 PH domain to promote 14-3-3 binding and PIP3 dissociation (PMID:35318320), SPOP-mediated ubiquitin–proteasome degradation primed by CK1/GSK3β phosphorylation of a degron (PMID:34353330), and Smurf1-mediated neddylation that assembles a cytoplasmic PDK1–Smurf1–SETDB1 complex directing Akt membrane attachment (PMID:39039255). Beyond catalysis, PDK1 acts as a scaffold, competing with RhoE for ROCK1 binding to control amoeboid motility (PMID:18204440), binding MRCKα to direct epithelial migration (PMID:25092657), and nucleating PKCθ/CARD11 assembly for TCR-induced NF-κB activation (PMID:15802604). In vivo, PDK1 is essential for embryonic development and cell-size control (PMID:12110585), T cell differentiation (PMID:15077109), endothelial migration and cardiac valve EMT (PMID:17371830, PMID:20457809), cardiac homeostasis (PMID:19429709), and platelet activation (PMID:23444402, PMID:29575487).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Established PDK1 as the lipid-regulated kinase that links PI3K signaling to Akt activation, answering how PIP3 generation is converted into a kinase-activating phosphorylation.

    Evidence Cloning, in vitro kinase assays with PIP3-containing vesicles, and PH domain deletion mutants in 293 cells; biochemical cascade dissection with wortmannin

    PMID:9247112 PMID:9368760

    Open questions at the time
    • Did not resolve the structural basis of PDK1 autoactivation
    • Did not establish substrate selectivity mechanisms beyond Akt
  2. 1998 High

    Broadened PDK1's substrate repertoire beyond Akt to p70S6K and PKC isoforms, showing it acts as a general activation-loop kinase for the AGC family.

    Evidence In vitro kinase assays with site identification (S6K Thr229, PKCζ Thr410), dominant-negative overexpression, and co-immunoprecipitation in HEK293 cells

    PMID:9445476 PMID:9748166 PMID:9768361

    Open questions at the time
    • Did not explain how PDK1 docks substrates that lack PH domains
    • Did not distinguish PIP3-dependent from PIP3-independent substrate engagement
  3. 1999 High

    Used yeast Pkh1/2 to show the PDK1 activation mechanism is conserved and that some substrates (SGK/Ypk1, Pkc1) are activated independently of PIP3, foreshadowing distinct docking modes.

    Evidence Genetic complementation, in vitro kinase assays with purified proteins, and epistasis in yeast

    PMID:10074427 PMID:10567559

    Open questions at the time
    • Did not define the molecular docking surface used for PIP3-independent substrates
    • Conservation in mammalian cells inferred, not directly tested for all substrates
  4. 2001 High

    Genetic dissection in Drosophila placed PDK1 as a growth controller acting through both Akt and S6K, with selective requirement for RSK but not PKN activation.

    Evidence Drosophila genetic epistasis and double-mutant analysis

    PMID:11752451

    Open questions at the time
    • Genetic interaction does not establish direct phosphorylation of each substrate in vivo
    • Mammalian substrate hierarchy not directly addressed
  5. 2002 High

    Defined the organismal role of PDK1 by showing it is essential for embryogenesis and that its dosage controls cell size independently of cell number.

    Evidence Knockout and hypomorphic mouse models with cell-volume measurement and in vivo insulin stimulation

    PMID:12110585

    Open questions at the time
    • Did not pinpoint which downstream substrate mediates cell-size control
    • Retained Akt/S6K/RSK activation in hypomorphs left effector ambiguous
  6. 2004 High

    Resolved the structural basis of small-molecule selectivity for PDK1 versus PKC and revealed in vivo requirements for T cell development.

    Evidence X-ray crystallography with bisindolyl maleimide inhibitors plus mutagenesis; conditional knockout in mouse thymocytes

    PMID:14962382 PMID:15077109

    Open questions at the time
    • Inhibitor structures did not address allosteric regulation outside the ATP site
    • T cell phenotype did not identify the critical PDK1 substrate
  7. 2005 High

    Uncovered a scaffolding, signal-nucleating role for PDK1 in TCR-induced NF-κB activation distinct from its activation-loop kinase function.

    Evidence Lipid raft fractionation, reciprocal co-immunoprecipitation, knockdown, and NF-κB reporter assays in T cells

    PMID:15802604

    Open questions at the time
    • Did not separate catalytic from scaffold contribution in this pathway
    • Mechanism of signal-dependent raft recruitment not fully defined
  8. 2006 High

    Demonstrated that the PIF/HM pocket is an allosteric activation site, providing a pharmacological route to switch PDK1 on.

    Evidence PIF-pocket mutagenesis, compound analog synthesis, and isothermal titration calorimetry

    PMID:17110931

    Open questions at the time
    • Physiological ligand for the pocket in cells not identified
    • Did not link pocket occupancy to specific substrate outputs
  9. 2008 High

    Genetically separated the two PDK1 docking mechanisms in vivo, showing the PIF-pocket is required for all substrates except Akt, whose activation needs PH-domain PIP3 binding.

    Evidence Knock-in mice carrying PIF-pocket and PH-domain point mutations with substrate phosphorylation analysis; plus a non-catalytic ROCK1-competition mechanism shown by direct binding and kinase-dead rescue

    PMID:18204440 PMID:18802401

    Open questions at the time
    • Did not address how individual non-Akt substrates compete for the single PIF pocket
    • Scaffold mechanism mapped for ROCK1 but generality untested
  10. 2009 Medium

    Expanded PDK1 regulation to reciprocal control with ASK1 and to upstream tyrosine-phosphorylation/in vivo functions in chemotaxis, defining bidirectional crosstalk and tissue roles.

    Evidence Co-IP and domain mapping with kinase-dead mutants (ASK1); siRNA knockdown and human primary-cell chemotaxis assays (neutrophils); earlier Src/Pyk2 tyrosine-phosphorylation mapping in smooth muscle cells

    PMID:14585963 PMID:19892919 PMID:19920149

    Open questions at the time
    • ASK1 reciprocal phosphorylation shown in a single lab without independent reciprocal validation
    • Tyrosine-phosphorylation cascade not confirmed in other cell types
  11. 2010 High

    Established PDK1's developmental and homeostatic requirements in the cardiovascular system, placing it upstream of Akt-Snail in cardiac EMT and of β1-AR trafficking in adult heart.

    Evidence Conditional endothelial and inducible cardiac knockout mice with adenoviral Akt, Snail mutant, PTEN-epistasis, and PI3Kγ-domain rescue experiments

    PMID:17371830 PMID:19429709 PMID:20457809

    Open questions at the time
    • Did not determine whether PDK1 phosphorylates Snail regulators directly
    • Tissue-specific effector selection mechanism unresolved
  12. 2014 Medium

    Consolidated PDK1's catalysis-independent scaffolding in cell migration, binding MRCKα and integrin αvβ3 to control protrusion dynamics and focal adhesion turnover.

    Evidence Co-IP, kinase-dead and PH-domain mutant rescue, co-localization imaging (MRCKα); siRNA, in vitro kinase assay, and endocytosis/FA-dynamics imaging (integrin αvβ3)

    PMID:25092657 PMID:25588838

    Open questions at the time
    • Integrin αvβ3 phosphorylation site and downstream coupling shown by a single lab
    • Relative contribution of scaffold vs catalytic activity across migration contexts not unified
  13. 2016 Medium

    Extended PDK1 to control of asymmetric cell division/epidermal differentiation and to CDK1-driven pluripotency, linking spatial PIP3 cues and cell-cycle kinases to PDK1 output.

    Evidence Conditional epidermal KO with aPKC/PAR3 localization and Notch rescue; CDK1 inhibition with PDK1 phosphorylation readout and Akt-effector epistasis in hESCs

    PMID:27184845 PMID:27636107

    Open questions at the time
    • CDK1-PDK1 phosphorylation site not mapped
    • aPKC-Notch axis causality inferred from rescue, single lab
  14. 2018 High

    Defined PDK1's role in platelet biology through Akt/GSK3β outside-in signaling and Raf1/MAPK-driven thromboxane generation, establishing it as a thrombosis regulator.

    Evidence Platelet-specific KO mice, pharmacological inhibition (BX-795), phosphorylation western blots, GSK3β-inhibitor rescue, and in vivo thrombosis/pulmonary embolism models

    PMID:23444402 PMID:29575487

    Open questions at the time
    • Direct PDK1 substrate in the Raf1/MAPK arm not identified
    • Whether GSK3β and MAPK arms are coupled or parallel unresolved
  15. 2020 High

    Linked PDK1 to metabolic disease by showing an adipocyte PDK1-FoxO1-5-LO/LTB4 axis controls systemic insulin sensitivity.

    Evidence Adipocyte-specific PDK1/FoxO1 double knockout mice, lipidomics, microarray, and BLT1/5-LO pharmacological blockade

    PMID:32393635

    Open questions at the time
    • Did not establish whether PDK1 controls FoxO1 solely via Akt
    • Human relevance of the LTB4 axis not tested
  16. 2021 High

    Identified two opposing post-translational regulatory layers: an mTORC1-S6K1 feedback loop that suppresses Akt activation, and SPOP-mediated degradation primed by CK1/GSK3β phosphorylation, both perturbed by cancer mutations.

    Evidence In vitro kinase assays with MS site mapping, Co-IP (14-3-3, AKT), PIP3-binding assays (S6K1 feedback); CRISPR E3-ligase screen, in vitro ubiquitination, degron kinase assay, and xenografts (SPOP)

    PMID:34353330 PMID:35318320

    Open questions at the time
    • Stoichiometry and dynamics of feedback vs degradation in cells not integrated
    • Whether the two layers act on the same PDK1 pool unknown
  17. 2022 High

    Provided the structural mechanism of PDK1 autoactivation as a PIP3-driven face-to-face dimer with linker-mediated allostery and PH-domain autoinhibition relieved by cooperative PIP3 binding.

    Evidence Structural/cryo-EM analysis, linker-motif mutagenesis, PIP3 cooperativity, and trans-autophosphorylation assays

    PMID:35387990

    Open questions at the time
    • Dimer prevalence and lifetime at native membranes not quantified
    • How dimerization is coordinated with substrate handoff unresolved
  18. 2024 High

    Revealed Smurf1-driven PDK1 neddylation as a signal that assembles a cytoplasmic PDK1-Smurf1-SETDB1 complex (cCOMPASS) directing Akt membrane attachment and tumorigenesis.

    Evidence Co-IP, neddylation assay, MS, Smurf1 KO mouse model, and a Smurf1 degrader compound with in vitro reconstitution

    PMID:39039255

    Open questions at the time
    • How SETDB1 methyltransferase activity contributes mechanistically not fully defined
    • Relationship of neddylation to PIP3-driven dimerization unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PDK1's multiple regulatory inputs—PIP3-dimerization, PIF-pocket docking, S6K1 feedback, ubiquitination, and neddylation—are integrated to select among 23 substrates in a given cell, and whether tissue-specific phenotypes reflect distinct substrate hierarchies.
  • No unified model linking each regulatory layer to specific substrate output
  • Substrate selection logic across tissues not established
  • Quantitative interplay of competing post-translational modifications unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-109582 Hemostasis 2 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2
Partners
AKT1CDC42BPAITGB3MAP3K5PRKCZROCK1RPS6KB1YWHAZ
Complex memberships
cCOMPASS (PDK1-Smurf1-SETDB1)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PDK1 is a 556-residue monomeric serine/threonine kinase comprising a catalytic domain (most similar to PKA/PKB/PKC subfamily) and a C-terminal pleckstrin homology (PH) domain. PDK1 phosphorylates PKB/Akt at Thr308 only in the presence of lipid vesicles containing PtdIns(3,4,5)P3 or PtdIns(3,4)P2. Deletion of the PH domain of PKBα prevents its phosphorylation by PDK1, indicating that PtdIns(3,4,5)P3/PtdIns(3,4)P2 binding to PKB is required for PDK1-mediated phosphorylation. Cloning/sequencing, in vitro kinase assay, PH domain deletion mutants, overexpression in 293 cells Current biology : CB High 9368760
1997 PDK1 sits at the hub of an insulin-stimulated kinase cascade downstream of PI3K: PtdIns(3,4,5)P3/PtdIns(3,4)P2 activate PDK1, which activates PKB, which inactivates GSK3, leading to glycogen synthase activation and glycogen synthesis. Biochemical cascade dissection, inhibitor studies (wortmannin), in vitro kinase assays FEBS letters High 9247112
1998 PDK1 phosphorylates and activates p70S6K at Thr229 (the activation-loop site), activating p70S6K in vitro and in vivo; catalytically inactive PDK1 blocks insulin-induced p70S6K activation. In vitro kinase assay, site-directed mutagenesis, dominant-negative overexpression in cells Science (New York, N.Y.) High 9445476
1998 PDK1 phosphorylates the activation-loop sites of PKCζ (Thr410) and PKCδ in vitro and in a PI3K-dependent manner in vivo. All PKC family members tested form complexes with PDK1. PDK1-dependent PKCδ phosphorylation in vitro is stimulated by combined PKC and PDK1 activators. In vitro kinase assay, co-immunoprecipitation, overexpression in HEK293 cells, PI3K inhibitor studies Science (New York, N.Y.) / Current biology : CB High 9748166 9768361
1999 Yeast Pkh1/Pkh2 are functional PDK1 homologs: purified Pkh1 activates mammalian SGK and PKBα in vitro by phosphorylating the same activation-loop residue as PDK1, and activates Ypk1 by phosphorylating Thr504. Pkh1/2 act upstream of Ypk1/Ykr2 (SGK homologs) in an essential two-tier kinase cascade. Unlike PKB activation, Ypk1/SGK activation by Pkh1 does not require PIP3, consistent with absence of PH domains in these substrates. Genetic complementation in yeast, in vitro kinase assay with purified proteins, epistasis analysis Current biology : CB High 10074427
1999 Yeast PDK1 homolog Pkh2 phosphorylates Pkc1 in vitro at Thr983 (a conserved PDK1 target motif in the activation loop); pkh1/pkh2 double mutants show reduced Pkc1 activity and phenocopy Pkc1-MAPK pathway mutants, placing Pkh1/2 upstream of Pkc1 in the Pkc1-MAPK cascade. In vitro kinase assay, genetic epistasis, temperature-sensitive mutant analysis Molecular and cellular biology High 10567559
2002 Genetic inactivation of PDK1 in mice causes embryonic lethality at E9.5 with multiple developmental defects. PDK1 hypomorphic mice (expressing ~10% normal PDK1) are viable but 40–50% smaller, with proportionally reduced organ volumes and reduced cell volume (35–60%), without affecting cell number, nuclear size, or proliferation. PDK1 deficiency does not affect insulin-induced activation of PKB, S6K, or RSK in hypomorphic mice. Knockout and hypomorphic mouse models, cell volume measurements, in vivo insulin stimulation The EMBO journal High 12110585
2003 PDK1 is tyrosine-phosphorylated by angiotensin II stimulation in vascular smooth muscle cells via a cascade where Pyk2 acts as scaffold for Src-dependent phosphorylation of PDK1 at Tyr9, enabling subsequent phosphorylation of Tyr373/376 by Src. Tyr9 phosphorylation is required for angiotensin II-induced tyrosine phosphorylation of paxillin and focal adhesion formation. Site-directed mutagenesis, dominant-negative overexpression, co-localization, angiotensin II stimulation of smooth muscle cells Molecular and cellular biology Medium 14585963
2004 PDK1 is essential for T cell differentiation in the thymus; complete PDK1 loss blocks T cell differentiation, while reduced PDK1 expression (to 10% normal) permits differentiation but blocks proliferative expansion. Conditional genetic knockout in mice, T cell developmental analysis Nature immunology High 15077109
2004 Crystal structures of the PDK1 kinase domain co-crystallized with bisindolyl maleimide inhibitors (LY333531, BIM-1/2/3/8) reveal their non-planar conformation within the ATP-binding site; combined with site-directed mutagenesis and essential dynamics analysis, the structural basis of inhibitor selectivity for PDK1 vs PKC was defined. X-ray crystallography, site-directed mutagenesis, essential dynamics analysis Structure (London, England : 1993) High 14962382
2005 PDK1 is required for TCR-induced NF-κB activation: PDK1 nucleates a signaling complex by recruiting PKCθ and CARD11 to lipid rafts in a signal-dependent manner. PDK1-associated PKCθ recruits the IKK complex, while PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, enabling NEMO ubiquitination and IKK activation. Genetic knockdown, lipid raft fractionation, co-immunoprecipitation, NF-κB reporter assays in T cells Science (New York, N.Y.) High 15802604
2006 Low molecular weight compounds targeting the hydrophobic motif (HM)/PIF-pocket of PDK1 allosterically activate PDK1 by modulating phosphorylation-dependent conformational transitions. Mutagenesis of the PIF-pocket abolished compound effects, and isothermal titration calorimetry confirmed direct binding. PIF-pocket mutagenesis, synthesis of compound analogs, interaction-displacement studies, isothermal titration calorimetry The EMBO journal High 17110931
2007 PDK1 is essential for vascular endothelial cell migration in response to VEGF-A. PDK1-null ECs derived from embryonic stem cells completely lose migration ability. PDK1 and Akt co-localize at the leading edge of polarized ECs following PI3K activation, establishing spatial control of directional chemotaxis. PDK1-null ES cell-derived ECs, in vitro migration assays, live imaging/co-localization The Journal of cell biology High 17371830
2008 PDK1 regulates cancer cell amoeboid motility through a non-catalytic mechanism: PDK1 directly binds ROCK1 at the plasma membrane and competes with RhoE for ROCK1 binding. In the absence of PDK1, RhoE-mediated inhibition of ROCK1 predominates, reducing acto-myosin contractility, myosin light chain phosphorylation, and cell motility. PDK1 knockdown, direct binding assay (PDK1-ROCK1 interaction), kinase-dead PDK1 rescue, in vivo motility assay Nature cell biology High 18204440
2009 PDK1 and ASK1 directly interact through the PH domain of PDK1 and the C-terminal regulatory domain of ASK1. Wild-type PDK1 (but not kinase-dead PDK1) phosphorylates ASK1 at Ser967 (a 14-3-3 binding site), suppressing ASK1 activity, AP-1 transactivation, and H2O2-induced apoptosis. Conversely, ASK1 phosphorylates PDK1 at Ser394/Ser398 to inhibit PDK1 function, establishing reciprocal negative regulation. Co-immunoprecipitation, domain mapping, kinase-dead mutants, in vitro phosphorylation, apoptosis assays The Journal of biological chemistry Medium 19920149
2009 Cardiac-specific inducible deletion of PDK1 in adult mice causes lethal heart failure with cardiomyocyte apoptosis and β1-adrenergic receptor (AR) down-regulation. PDK1-deficient hearts show enhanced PI3Kγ activity, leading to robust β1-AR internalization via a βARK1/PI3Kγ complex; interference with this complex (by transgenic overexpression of the PI3Kγ kinase domain) normalizes β1-AR trafficking and improves cardiac function. Inducible cardiac-specific knockout mice, Bcl-2 overexpression rescue, transgenic PI3Kγ domain overexpression, receptor trafficking assays Proceedings of the National Academy of Sciences of the United States of America High 19429709
2010 Endothelial-specific PDK1 deletion in mice causes embryonic lethality (~E11.5) with defective vascular remodeling and failure of atrioventricular cushion/valve formation (EMT defect). Mechanistically, PDK1 loss reduces Snail nuclear localization; delivery of Snail S6A mutant or adenoviral Akt rescued EMT defects in AVC explants. PTEN deletion delayed lethality and normalized AVC development in PDK1-deficient hearts, placing PDK1 upstream of Akt-Snail in cardiac EMT. Conditional endothelial KO mice, ex vivo AVC explant rescue, adenoviral Akt delivery, genetic epistasis with PTEN Molecular and cellular biology High 20457809
2013 PDK1 regulates platelet activation by controlling αIIbβ3-mediated outside-in signaling. PDK1 deficiency abolishes Akt Thr308 phosphorylation and GSK3β Ser9 phosphorylation in response to agonists; a GSK3β inhibitor fully restores aggregation, spreading, and clot retraction in PDK1-null platelets, identifying GSK3β as a major downstream effector of PDK1 in platelet outside-in signaling. Platelet-specific PDK1 KO mice, phosphorylation western blot, pharmacological GSK3β inhibition rescue, in vivo thrombosis model Blood High 23444402
2014 PDK1 binds and activates MRCKα (myotonic dystrophy kinase-related CDC42-binding kinase α) to regulate directional epithelial cell migration. This interaction is PI3K-dependent (requires PIP3 binding by PDK1) but does not require PDK1 kinase activity. PDK1 and MRCKα co-localize at lamellipodia upon EGF stimulation, and PDK1 controls lamellipodia retraction through MRCKα-dependent myosin contraction. Co-immunoprecipitation, kinase-dead mutant rescue, PH domain mutant, co-localization imaging, MRCKα activity assay The Journal of cell biology High 25092657
2015 PDK1 promotes focal adhesion (FA) turnover in endothelial cells by binding and phosphorylating integrin αvβ3, promoting its endocytosis in a PI3K-dependent manner. PDK1 silencing increases FA size, slows FA disassembly, stabilizes FA in membrane protrusions, and decreases endothelial cell migration on vitronectin; this requires PDK1 kinase activity but not Akt. PDK1 siRNA knockdown, Co-IP (PDK1-integrin αvβ3), in vitro kinase assay, FA dynamics imaging, endocytosis assay Journal of cell science Medium 25588838
2016 PDK1 regulates asymmetric cell division (ACD) and epidermal differentiation. PIP3 is localized to the apical side of basal cells; PDK1 conditional KO impairs asymmetric recruitment of aPKC and PAR3. PDK1-null keratinocytes fail to activate aPKC upon calcium stimulation or activate Akt upon IGF1, and show decreased Notch expression; Notch restoration rescues differentiation defects, placing PDK1 upstream of aPKC-Notch in ACD. Conditional KO epidermis, immunofluorescence for aPKC/PAR3 localization, Notch restoration rescue experiments Cell reports Medium 27184845
2018 PDK1 governs thromboxane generation and ADP-induced platelet activation by regulating Raf1 activation in the MAPK pathway. PDK1 inhibition (BX-795) or genetic ablation prevents phosphorylation of MEK1/2, ERK1/2, cPLA2, and Raf1, thereby blocking thromboxane synthesis. PDK1 genetic ablation protects mice from collagen/epinephrine-induced pulmonary embolism. Platelet-specific PDK1 KO mice, pharmacological PDK1 inhibition, phosphorylation western blot, in vivo pulmonary embolism model Journal of thrombosis and haemostasis : JTH High 29575487
2021 S6K1 directly phosphorylates PDK1 at its PH domain, augmenting PDK1 interaction with 14-3-3 adaptor protein and PDK1 homo-dimerization, which dissociates PDK1 from PIP3 and reduces its interaction with and activation of AKT. This constitutes a negative feedback loop (mTORC1→S6K1→phospho-PDK1→reduced AKT) that attenuates AKT signaling. In vitro kinase assay (S6K1 phosphorylating PDK1), mass spectrometry site identification, Co-IP (PDK1-14-3-3, PDK1-AKT), PIP3 binding assay, cancer patient mutation analysis Nature communications High 35318320
2021 SPOP E3 ubiquitin ligase mediates ubiquitination and proteasome-dependent degradation of PDK1. SPOP directly binds PDK1 via a consensus degron in a CK1/GSK3β-mediated phosphorylation-dependent manner. Prostate cancer-associated SPOP mutations impair PDK1 degradation, elevating AKT kinase activity. CRISPR-based E3 ligase screen, Co-IP, in vitro ubiquitination assay, in vitro kinase assay (CK1/GSK3β phosphorylating PDK1 degron), xenograft mouse models Molecular cancer High 34353330
2022 PDK1 auto-activation is driven by PIP3-mediated dimerization: PDK1 trans-autophosphorylation is mediated by a PIP3-driven face-to-face dimer. Regulatory motifs in the kinase-PH interdomain linker allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. PDK1 is autoinhibited by its PH domain, and positive cooperativity of PIP3 binding drives switch-like activation. Cryo-EM/structural analysis, mutagenesis of linker regulatory motifs, PIP3 binding cooperativity assays, trans-autophosphorylation assays Nature communications High 35387990
2024 E3 ligase Smurf1 triggers PDK1 neddylation upon growth factor stimulation; poly-Nedd8 chains on PDK1 recruit methyltransferase SETDB1, forming a cytoplasmic complex (cCOMPASS: PDK1-Smurf1-SETDB1) that directs Akt membrane attachment and Thr308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Co-IP, neddylation assay, mass spectrometry, genetic mouse model (Smurf1 KO), Smurf1 degrader compound, in vitro reconstitution Nature chemical biology High 39039255
2008 PDK1 PIF-pocket (substrate docking site) is required for activation of all PDK1 substrates except PKB/Akt; PH domain binding to PtdIns(3,4,5)P3 is essential for efficient PKB activation and normal cell size/insulin sensitivity, but not required for other substrate activation. PDK1 knock-in mice with PIF-pocket and PH domain mutations, biochemical analysis of substrate phosphorylation Cell cycle (Georgetown, Tex.) High 18802401
2001 In Drosophila, dPDK1 controls cellular and organismal growth by activating both dAkt and dS6K. Genetic interaction studies show dPDK1 genetically interacts with dRSK but not dPKN, suggesting dPDK1 is required for dRSK (but not dPKN) activation in vivo. Drosophila genetic epistasis, loss-of-function and gain-of-function analysis, double mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 11752451
2009 PDK1 is essential for neutrophil chemotaxis: PDK1 siRNA knockdown significantly reduces chemotaxis without affecting superoxide generation. Reduced PDK1 expression and activation in neutrophils from patients with localized aggressive periodontitis correlates with reduced Akt Thr308 phosphorylation and impaired chemotaxis. PDK1 siRNA knockdown, neutrophil chemotaxis assay, phosphorylation western blot, pharmacological inhibition (staurosporine) Journal of dental research Medium 19892919
2016 CDK1 phosphorylates PDK1 and consequently modulates PI3K/Akt activity and its effectors ERK and GSK3β; reducing CDK1 activity induces differentiation of human embryonic stem cells through this pathway. Reversion of CDK1-inhibited differentiation by Akt signaling effector inhibition confirms the CDK1-PDK1-PI3K/Akt cascade is functional for pluripotency maintenance. CDK1 inhibition (no cell cycle effect dose), phosphorylation analysis of PDK1, epistasis with Akt signaling inhibitors, hESC differentiation assays Cell death and differentiation Medium 27636107
2020 In adipocytes, PDK1 regulates FoxO1 to suppress 5-lipoxygenase (5-LO) expression and leukotriene B4 (LTB4) production. Adipocyte-specific PDK1 KO mice develop systemic insulin resistance that is rescued by additional FoxO1 deletion; lipidomics identified elevated LTB4 in A-PDK1KO mice restored to normal in A-PDK1/FoxO1KO mice. Genetic or pharmacological blockade of LTB4 or its receptor BLT1 ameliorated insulin resistance in A-PDK1KO mice. Adipocyte-specific PDK1 and FoxO1 double KO mice, lipidomics, microarray, BLT1/5-LO pharmacological inhibition, isolated adipocyte experiments Proceedings of the National Academy of Sciences of the United States of America High 32393635
2023 Pyruvate dehydrogenase kinase 1 (PDK1, the metabolic enzyme) phosphorylates HIF-1α at Ser451, stabilizing its protein levels by inhibiting HIF-1α interaction with VHL and prolyl hydroxylase domain proteins, and enhancing HIF-1α transcriptional activity by promoting its binding to P300. HIF-1α phosphorylation at Ser451 was detected in WT breast cancer cells but not in PDK1 KO cells. PDK1 KO cell lines, in vitro kinase assay, co-immunoprecipitation (HIF-1α with VHL/PHD, HIF-1α with P300), ubiquitination assay, phosphorylation site identification Genes & diseases Medium 38560503

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The PI3K-PDK1 connection: more than just a road to PKB. The Biochemical journal 1196 10698680
1998 Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science (New York, N.Y.) 941 9748166
1998 Phosphorylation and activation of p70s6k by PDK1. Science (New York, N.Y.) 736 9445476
2004 PDK1, the master regulator of AGC kinase signal transduction. Seminars in cell & developmental biology 666 15209375
1997 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Current biology : CB 620 9368760
1998 Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Current biology : CB 538 9768361
2015 PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer. Cell metabolism 467 26365179
2002 Essential role of PDK1 in regulating cell size and development in mice. The EMBO journal 276 12110585
1997 PDK1, one of the missing links in insulin signal transduction? FEBS letters 229 9247112
1999 Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Current biology : CB 225 10074427
2008 PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nature cell biology 217 18204440
2017 Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene 210 29106390
2005 PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation. Science (New York, N.Y.) 198 15802604
1999 Intracellular signalling: PDK1--a kinase at the hub of things. Current biology : CB 176 10021376
2017 PDK1: At the crossroad of cancer signaling pathways. Seminars in cancer biology 161 28473254
2001 PDK1 regulates growth through Akt and S6K in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 141 11752451
2005 Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice. Current biology : CB 130 16243031
2011 Targeting PDK1 in cancer. Current medicinal chemistry 127 21568903
1999 PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast. Molecular and cellular biology 120 10567559
2001 IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Archiv : European journal of physiology 117 11907830
2018 EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy. Cell death & disease 108 29449645
2008 Small-molecule inhibitors of PDK1. ChemMedChem 108 18972468
2019 lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway. Molecular oncology 102 31368655
2004 The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nature immunology 100 15077109
2006 Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. The EMBO journal 97 17110931
2016 CDK1-PDK1-PI3K/Akt signaling pathway regulates embryonic and induced pluripotency. Cell death and differentiation 93 27636107
2010 PDK1: the major transducer of PI 3-kinase actions. Current topics in microbiology and immunology 93 20563709
2020 The Implications of PDK1-4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance. Frontiers in oncology 87 33384955
2015 PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness. The Journal of experimental medicine 84 25624444
2008 Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell cycle (Georgetown, Tex.) 80 18802401
2015 PDK1: A signaling hub for cell migration and tumor invasion. Biochimica et biophysica acta 76 26238471
2013 PDK1 regulates platelet activation and arterial thrombosis. Blood 75 23444402
2022 Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation. Nature communications 74 35387990
2021 SPOP-mediated ubiquitination and degradation of PDK1 suppresses AKT kinase activity and oncogenic functions. Molecular cancer 72 34353330
2018 MiR-155-5p inhibits PDK1 and promotes autophagy via the mTOR pathway in cervical cancer. The international journal of biochemistry & cell biology 71 29627439
2003 Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Molecular and cellular biology 71 14585963
2007 Essential role of PDK1 in regulating endothelial cell migration. The Journal of cell biology 70 17371830
2004 Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1. Structure (London, England : 1993) 68 14962382
2014 MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. International journal of molecular medicine 64 24481267
2009 Cell type specificity of PI3K signaling in Pdk1- and Pten-deficient brains. Genes & development 63 19605683
2022 S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions. Nature communications 62 35318320
2017 Serine/Threonine Kinase 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) as a Key Regulator of Cell Migration and Cancer Dissemination. Cancers 62 28287465
2005 Adi3 is a Pdk1-interacting AGC kinase that negatively regulates plant cell death. The EMBO journal 62 16362044
2017 CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget 56 29029419
2013 Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene 56 24037523
2016 MicroRNA-379 suppresses osteosarcoma progression by targeting PDK1. Journal of cellular and molecular medicine 55 27781416
2006 3-phosphoinositide-dependent protein kinase-1 (PDK1) promotes invasion and activation of matrix metalloproteinases. BMC cancer 52 16551362
2020 HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway. Frontiers in endocrinology 51 32047474
2020 Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 51 33229519
2015 PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets. Cancer research 50 25712345
2010 PDK1 regulates vascular remodeling and promotes epithelial-mesenchymal transition in cardiac development. Molecular and cellular biology 50 20457809
2005 "New"-clear functions of PDK1: beyond a master kinase in the cytosol? Journal of cellular biochemistry 50 16187290
2017 SOX9-PDK1 axis is essential for glioma stem cell self-renewal and temozolomide resistance. Oncotarget 49 29416606
2019 PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 46 30770351
2014 PDK1 regulates B cell differentiation and homeostasis. Proceedings of the National Academy of Sciences of the United States of America 46 24979759
2007 The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 45 17255356
2018 PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway. Journal of thrombosis and haemostasis : JTH 44 29575487
2016 PDK1-Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex. Proceedings of the National Academy of Sciences of the United States of America 44 27170189
2022 Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 35064767
2013 PDK1 controls upstream PI3K expression and PIP3 generation. Oncogene 43 23893244
2011 Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Journal of medicinal chemistry 42 21341675
2018 Discoidin Domain Receptor 2 Signaling Regulates Fibroblast Apoptosis through PDK1/Akt. American journal of respiratory cell and molecular biology 41 29652518
2009 PDK1 coordinates survival pathways and beta-adrenergic response in the heart. Proceedings of the National Academy of Sciences of the United States of America 39 19429709
2003 PDK1 and PKB/Akt: ideal targets for development of new strategies to structure-based drug design. IUBMB life 39 12822887
2023 Master kinase PDK1 in tumorigenesis. Biochimica et biophysica acta. Reviews on cancer 35 37640147
2020 The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B4 axis. Proceedings of the National Academy of Sciences of the United States of America 35 32393635
2014 Emerging role of the KRAS-PDK1 axis in pancreatic cancer. World journal of gastroenterology 34 25152578
2021 The kinase PDK1 regulates regulatory T cell survival via controlling redox homeostasis. Theranostics 33 34646383
2017 Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma. Oncotarget 33 28410193
2017 The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway. Scientific reports 33 28878225
2013 PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. The EMBO journal 33 23463102
2009 Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation. The Journal of biological chemistry 33 19920149
2016 PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division. Cell reports 32 27184845
2014 PDK1-mediated activation of MRCKα regulates directional cell migration and lamellipodia retraction. The Journal of cell biology 32 25092657
2017 Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma. Cancers 30 28430130
2019 The double inhibition of PDK1 and STAT3-Y705 prevents liver metastasis in colorectal cancer. Scientific reports 29 31506552
2024 FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions. Journal of advanced research 28 39701379
2021 TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway. Cell death & disease 28 34789718
2015 PDK1 induces JunB, EMT, cell migration and invasion in human gallbladder cancer. Oncotarget 28 26318166
2013 Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1. Journal of medicinal chemistry 28 23448267
2024 Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer. Nature chemical biology 25 39039255
2014 Acute regulation of PDK1 by a complex interplay of molecular switches. Biochemical Society transactions 25 25233428
2010 PI3 kinase and PDK1 in the regulation of the electrogenic intestinal dipeptide transport. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 20511717
2009 PDK1 regulates chemotaxis in human neutrophils. Journal of dental research 25 19892919
2015 PDK1-mTOR signaling pathway inhibitors reduce cell proliferation in MK2206 resistant neuroblastoma cells. Cancer cell international 24 26421002
2013 The kinase PDK1 is essential for B-cell receptor mediated survival signaling. PloS one 24 23393571
2024 Lactate accumulation induced by Akt2-PDK1 signaling promotes pulmonary fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 38226859
2017 S-Nitrosylation inhibits the kinase activity of tomato phosphoinositide-dependent kinase 1 (PDK1). The Journal of biological chemistry 23 28972151
2015 PDK1 regulates focal adhesion disassembly by modulating endocytosis of αvβ3 integrin. Journal of cell science 23 25588838
2014 Immunohistochemical analysis of PDK1 expression in breast cancer. Diagnostic pathology 23 24739482
2012 PDK1 inhibitors. Pharmaceutical patent analyst 23 24236780
2022 The Landscape of PDK1 in Breast Cancer. Cancers 22 35159078
2021 The kinase PDK1 is critical for promoting T follicular helper cell differentiation. eLife 22 33595435
2023 The choreography of protein kinase PDK1 and its diverse substrate dance partners. The Biochemical journal 21 37792325
2003 Expression pattern of the Rsk2, Rsk4 and Pdk1 genes during murine embryogenesis. Gene expression patterns : GEP 21 12711546
2023 S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway. Oncogene 20 37828220
2023 PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α. Genes & diseases 20 38560503
2022 PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer. Cancer & metabolism 20 36474273
2021 A novel PDK1 inhibitor, JX06, inhibits glycolysis and induces apoptosis in multiple myeloma cells. Biochemical and biophysical research communications 20 34875534
2019 Stage-specific requirement of kinase PDK1 for NK cells development and activation. Cell death and differentiation 20 30622306

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