3 phosphoinositide dependent protein kinases. Medical search. Frequent questions

PDK1 contains an N-terminal serine/threonine kinase domain followed by a PH domain. (embl.de)
The 90-kDa ribosomal S6 kinase (Rsk) is a family constituted by four isoforms (Rsk1-4) of serine/threonine kinases broadly expressed in the brain that regulate important cellular functions, including cell survival [ 1 ]. (biomedcentral.com)
All NSP proteins contain an NH 2 -terminal SH2 (Src homology domain 2) domain, a central proline/serine-rich domain, and a COOH-terminal domain with modest homology to Ras subfamily GDP-exchange factors (GEFs). (molvis.org)
A pyruvate dehydrogenase kinase isozyme located in the mitochondria which converts PYRUVATE to ACETYL CoA in the CITRIC ACID CYCLE, phosphorylates SERINE residues on pyruvate dehydrogenase using ATP, and plays a key role in the regulation of GLUCOSE and fatty acid metabolism. (bvsalud.org)

Fig. 1: Serum mitogen-induced phosphorylation of PI3KC2-β induces complex formation with 14-3-3 proteins. (nature.com)
Fig. 5: mTORC2 signalling triggers PKN2 activation to control PI3KC2-β phosphorylation and sequestration with 14-3-3 proteins. (nature.com)
The primary accession code for screening data used for identifying nutrient-dependent interaction partners and phosphorylation of PI3KC2-β is PXD014533 , the accession code for data used for identifying small Rab GTPases interacting with PI3KC2-β is PXD014530 . (nature.com)
Incubation of human monocytic THP-1 cells with LA induced phosphorylation of Akt in a time- and dose-dependent manner. (oregonstate.edu)
This LA-dependent increase in Akt phosphorylation was accompanied by inhibition of LPS-induced NF-kappaB DNA binding activity and up-regulation of TNFalpha and monocyte chemoattractant protein 1. (oregonstate.edu)
Lipoic acid-dependent Akt phosphorylation and inhibition of NF-kappaB activity were abolished by the PI3K inhibitors LY294002 and wortmannin. (oregonstate.edu)
Analysis of the phosphorylation of Rsk in Hdh mice and STHdh cells showed reduced levels of phospho Ser-380 (dependent on ERK1/2), whereas phosphorylation at Ser-221 (dependent on PDK1) was increased. (biomedcentral.com)
This phosphorylation allows the dockage of PDK1 to the hydrophobic motif and enables PDK1-dependent phosphorylation in the NTKD of Rsk at Ser-221, resulting in its maximal activation [ 1 , 4 ]. (biomedcentral.com)
Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of ErbB-2, resulting in the phosphorylation of both plexin-B1 and ErbB-2. (rupress.org)
The roles of PEP3/PtdInsTP and PEP1/PtdInsP5K in sequential phosphoinositide recruitment and phosphorylation explains their synergistic activity in ATP-dependent priming. (nih.gov)
The results indicate that lipid kinase-mediated phosphorylation is an important basis for ATP use in the exocytotic pathway. (nih.gov)
In healthy individuals, nicotine improves memory impairment caused by sleep deprivation by enhancing the phosphorylation of calmodulin‑dependent protein kinase II, an essential regulator of cell proliferation and synaptic plasticity. (spandidos-publications.com)
This phosphorylation is regulated by the ataxia telangiectasia mutated (ATM) and the Rad3-related (ATR) kinases in response to various genotoxic stresses, making it a critical regulatory element of DNA-PKcs ( 6 , 10 ). (amegroups.org)

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. (rcsb.org)
PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. (wikipedia.org)
PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. (wikipedia.org)
Glioblastoma (GBM), a very aggressive and incurable tumor, often results from constitutive activation of EGFR (epidermal growth factor receptor) and of phosphoinositide 3-kinase (PI3K). (sdbonline.org)
IRS proteins bind to the phosphorylated residues on the IR and subsequently recruit the regulatory subunit p85 of PI3K. (jci.org)
PI3K thereby becomes activated and phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP 2 ) on position 3′ in the inositol ring, generating PIP 3 . (jci.org)
Phosphoinositide 3-kinase (PI3K) takes a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. (chimia.ch)
The discovery of wortmannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the assembly of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. (chimia.ch)
The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was recently shown to negatively regulate LPS-induced acute inflammatory responses. (oregonstate.edu)
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is among the most integral pathways associated with cell metabolism, proliferation, differentiation, and success. (bioxorio.com)
Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. (aai.org)

By monitoring pairwise disulfide conjugation between PIFtide and PDK1 cysteine mutants, we defined the PIFtide binding orientation in the PIF pocket of PDK1 and assessed subtle relationships between PIFtide positioning and kinase activation. (rcsb.org)
This study reports that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. (sdbonline.org)
Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. (sdbonline.org)
The protein kinase B/AKT and phosphoinositide-dependent protein kinase 1 (PDK1) bind to PIP 3 via their pleckstrin homology (PH) domains. (jci.org)
This entry represents the pleckstrin homology (PH) domain from 3-phosphoinositide-dependent protein kinase 1 (PDK1) type proteins. (embl.de)
Following binding of the PH domain to PtdIns(3,4,5)P3 and PtdIns(3,4)P2, PDK1 activates these enzymes by phosphorylating a Ser/Thr residue in their activation loop. (embl.de)
Rsk activation is regulated by sequential phosphorylations controlled by extracellular signal-regulated kinase (ERK) 1/2 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). (biomedcentral.com)
BAG 956 is a dual PDPK1 (PDK1) and class I PI 3-K inhibitor (IC 50 values are 245, 56, 446, 35 and 117 nM for PDPK1 and PI 3-K p110 - α , - β , - δ , and - γ respectively). (tocris.com)

Losartan has protective effect on aortic wall of rats with aortic dissection, and the mechanism may be through inhibiting transforming growth factor-beta 1 pathway, which activates downstream phosphoinositide 3-kinase/protein kinase B pathway related proteins, and then inhibits the expansion and progression of aortic dissection. (ijpsonline.com)
It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK . (sdbonline.org)
Glucose metabolism activates this pathway by means of increasing [Ca 2+ ] i via L-type voltage-dependent calcium channels (VDCCs) by affecting the electrical activity of the cell. (diabetesjournals.org)
Next, we observed that Acanthamoeba specifically activates phosphatidylinositol 3-kinase. (asm.org)

The 90-kDa ribosomal S6 kinase (Rsk) family is involved in cell survival. (biomedcentral.com)

Here, we show that plexin-B family members stably associate with the receptor tyrosine kinase ErbB-2. (rupress.org)

PDPK1 (3 Phosphoinositide Dependent Protein Kinase 1) phosphorylates AGC kinases. (thermofisher.com)
PDPK1 also phosphorylates Protein Kinase B (PKB) at threonine 308 in the presence of phosphatidylinositol-3,4,5-trisphosphate. (thermofisher.com)
Active PKN2 phosphorylates PI3KC2-β to trigger PI3KC2-β complex formation with inhibitory 14-3-3 proteins. (nature.com)

The majority of inositol lipids reside in membranes and serve as substrates for kinases, phosphatases, and phospholipases. (asm.org)
How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3'-phosphorylated inositol lipids. (northwestern.edu)

There is significant interest in identifying and characterizing allosteric sites in enzymes such as protein kinases both for understanding allosteric mechanisms as well as for drug discovery. (rcsb.org)
At the International Centre for Kinase Profiling (ICKP) we understand that ascertaining how your compound behaves in relation to the multitude of related enzymes is critical. (mrc.ac.uk)
These enzymes include protein kinase B (PKB)/AKT and PtdIns(3,4,5)P 3 -dependent kinases 1 and 2, the first two of which interact with 3'-phosphorylated phosphoinositides via pleckstrin homology domains. (northwestern.edu)

We demonstrate that protein kinase N (PKN) facilitates mTORC1 signalling by repressing PI3KC2-β-mediated phosphatidylinositol-3,4-bisphosphate synthesis downstream of mTORC2. (nature.com)

Int J Immunogenet 2006(3): 205-9 [ PubMed abstract ]. (lu.se)
Eur J Pediatr 2006(3): 165-7 [ PubMed abstract ]. (lu.se)

We are also working on the discovery of DeltaFosB inhibitors, neurexin modulators, and FGF14/Nav1.6 channel complex protein-protein interaction inhibitors as CNS probes and potential therapeutics. (utmb.edu)
The response to GLP-1 was mimicked by forskolin and largely inhibited by the protein kinase A (PKA) inhibitors, H89 and myristoylated PKI(14-22) amide, indicating partial mediation via a cAMP/PKA pathway. (diabetesjournals.org)

PDPK1 is constitutively active and at present, there is no known inhibitor proteins for PDPK1. (wikipedia.org)
Significantly, the actions of both GLP-1 and forskolin were abolished by the selective Ca 2+ /calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, FK506, as well as by the chelation of intracellular Ca 2+ by BAPTA (bis(2-aminophenoxy)ethane- N,N,N ′ ,N ′-tetraacetate). (diabetesjournals.org)
BAG 956 is also offered as part of the Tocriscreen Kinase Inhibitor Library and Tocriscreen Antiviral Library . (tocris.com)
Acanthamoeba -mediated brain endothelial cell death was abolished using LY294002, a phosphatidylinositol 3-kinase inhibitor. (asm.org)
Inhibition of DNA-PKcs activity via a small interfering RNA or a kinase inhibitor results in mitosis delay, abnormal spindle formation, and chromosome misalignment. (amegroups.org)

These results uncover a mechanism that couples mTORC2-dependent activation of PKN2 to the regulation of mTORC1-mediated nutrient signalling by local lipid signals. (nature.com)
The lipid phosphatase PTEN antagonizes this by dephosphorylating PIP 3 to generate PIP 2 . (jci.org)
A study by White et al (2009) found that psychosine's cytotoxic effects on oligodendroglia and Schwann cells was mediated through disruption of the architecture and composition of lipid rafts (cell membrane regions characterized by high cholesterol and sphingolipid concentration), followed by altered protein kinase C (PKC) function. (medscape.com)

the activities of Ca2+/calmodulin (CaM)-dependent protein kinase (PK II) and Ca2+/phosphoinositide-dependent protein kinase (PKC) were assayed using histidine as substrate. (chinaphar.com)
This most likely occurs from defects in postreceptor insulin signal transduction at the level of insulin receptor substrate-1 and phosphoinositide (PI) 3-kinase ( 6 - 9 ) as well as defects in trafficking and/or function of GLUT4 ( 10 , 11 ), the major insulin-regulated GLUT isoform expressed in skeletal muscle ( 12 ). (diabetesjournals.org)
Binding to a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate. (planteome.org)

In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the PDPK1 gene in humans. (wikipedia.org)
PDPK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. (wikipedia.org)
PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1. (wikipedia.org)
The PH domain functions mainly in the interaction of PDPK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1's substrates including AKT. (wikipedia.org)
Several PDPK1 substrates including S6K and Protein kinase C, require the binding at this docking site. (wikipedia.org)
The activation of PDPK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane. (wikipedia.org)

Mechanistic target of rapamycin (mTOR) kinase functions in two multiprotein complexes: lysosomal mTOR complex 1 (mTORC1) and mTORC2 at the plasma membrane. (nature.com)
LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. (sdbonline.org)
Regulated fusion of secretory granules with the plasma membrane in secretory cells requires ATP, Ca2+ and cytosolic as well as membrane proteins. (nih.gov)
One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membrane-restricted second messenger, polyphosphatidylinositides containing a 3'-phosphate. (northwestern.edu)

We have previously identified NFAT (nuclear factor of activated T-cells) as a key regulator of insulin gene transcription in pancreatic β-cells that is activated by the calcium/calmodulin-dependent protein phosphatase 2B (calcineurin) in response to increased [Ca 2+ ] i ( 10 ). (diabetesjournals.org)

Active Akt inactivates Glycogen Synthase Kinase 3 (GSK3), eventually leading to the dephosphorylation and activation of glycogen synthase, and the stimulation of glycogen synthesis. (thermofisher.com)

A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt . (nature.com)
These data suggest that the synergistic action of glucose and GLP-1 to promote insulin gene transcription is mediated through NFAT via PKA- and calcineurin-dependent pathways in pancreatic β-cells. (diabetesjournals.org)
60% of human protein-coding genes, mostly by binding to the 3′- untranslated region (3′UTR) of the target mRNAs ( 5 ) and, therefore, miRNAs affect gene expression networks of a variety of biological processes including development, apoptosis, proliferation, and metabolism ( 1 , 2 ). (frontiersin.org)
Our aim is to explore approaches to collecting information from multiple sub-clinical traits (e.g., gene expression, protein levels, metabolite measurements) in search for loci responsible for complex diseases. (biomedcentral.com)

The master kinase LKB1 is a key regulator of several cellular processes, including cell proliferation, cell polarity and cellular metabolism. (sdbonline.org)

These studies show that disulfide trapping is useful for characterizing allosteric sites on kinases and that a single allosteric site on a protein kinase can be exploited for both activation and inhibition by small molecules. (rcsb.org)
The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interactions. (bvsalud.org)

RNA polymerase II mainly transcribes microRNA genes as primary miRNA transcripts (pri-miRNAs) that contain 5′cap and 3′poly(A) tails ( 28 ). (frontiersin.org)
To date, it is well known that lncRNAs participate in chromatin modifications and transcriptional and translational regulation of protein-encoding genes or regulate protein function and activity through specific binding [ 3 - 5 ]. (jcancer.org)
Genes that suppress carcinogenesis have been classified as gatekeepers that regulate cellular proliferation and cell death and as caretakers that are primarily encode DNA repair proteins required for the maintenance of genome integrity ( 15 ). (amegroups.org)
From experimentally validated target genes of these 86 miRNAs, pan-sensitive and pan-resistant genes with concordant mRNA and protein expression associated with in-vitro drug response to 19 NCCN-recommended breast cancer drugs were selected. (cdc.gov)
The mRNA and protein expression of the 26 genes was associated with sensitivity or resistance to 18 NCCN-recommended drugs for treating breast cancer. (cdc.gov)

the kinase or catalytic domain and the PH domain. (wikipedia.org)

Fig. 2: PKN2 facilitates mTORC1 activation by phosphorylating PI3KC2-β and triggering sequestration by 14-3-3 proteins. (nature.com)
AIM: To study the mechanism of K+ depolarization-induced activation of synaptosomal tyrosine 3-monooxygenase (TM) in rat striatum and the effect of (-)-stepholidine (SPD) on this activation. (chinaphar.com)
Glucose transport can be activated in skeletal muscle in response to insulin via activation of phosphoinositide (PI) 3-kinase and in response to contractions or hypoxia, presumably via activation of 5′ AMP-activated protein kinase (AMPK). (diabetesjournals.org)

More specifically, substrates with certain FYVE domains (named after the first four proteins in this motif, Fab1, YotB, Vac1p, and EEA1) bind PIP, and these pathways have been implicated in vesicular trafficking or receptor-mediated endocytosis ( 5 ). (asm.org)

In addition, downregulation of the V-ATPase subunit VhaPPA1-1 reduces Akt and Tor-dependent signaling and restores clearance. (sdbonline.org)
Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. (oregonstate.edu)
Phosphatidylinositol 3-kinases (PI3Ks) are important signaling molecules that phosphorylate the 3′ OH position of the inositol ring of phosphoinositides (PIs), generating the second messengers PI(3)P, PI(3,4)P 2 , and PI(3,4,5)P 3 ( 4 , 17 ). (asm.org)
In AD, nicotine improves cognitive impairment by enhancing protein kinase B (also referred to as Akt) activity and stimulating phosphoinositide 3‑kinase/Akt signaling, which regulates learning and memory processes. (spandidos-publications.com)
DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key component of the non-homologous end-joining (NHEJ) pathway, is involved in DNA double-strand break repair, immunocompetence, genomic integrity, and epidermal growth factor receptor signaling. (amegroups.org)
PKC isozymes are LR-dependent molecules that link psychosine-induced LR disruption to reduced PKC function and altered cell signaling activity, possibly driving demyelination and apoptosis in oligodendrocytes and Schwann cells. (medscape.com)
At the crossroads of fertility and metabolism: the importance of AMPK-dependent signaling in female infertility associated with hyperandrogenism. (who.int)

Identification of Bruton tyrosine kinase mutations in 12 Chinese patients with X-linked agammaglobulinaemia by long PCR-direct sequencing. (lu.se)

We determined the effects of insulin and muscle contraction/hypoxia on PI 3-kinase, AMPK, and glucose transport activity in epitrochlearis skeletal muscle from insulin-resistant Zucker ( fa/ fa ) rats. (diabetesjournals.org)

To investigate the effect of losartan on vascular remodeling and transforming growth factor-beta and phosphoinositide 3-kinase/protein kinase B pathway. (ijpsonline.com)
Hematoxylin and eosin staining was used to measure the thickness and diameter ratio of the aortic media of mice in each group, Masson staining was used to observe the content of collagen fibers in the aorta of mice in each group, elastic fibers in the aorta of mice in each group were stained, and transforming growth factor-beta and phosphoinositide 3-kinase/protein kinase B pathway protein expression. (ijpsonline.com)
The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is the key component of the non-homologous end-joining (NHEJ) pathway for DNA double-strand break (DSB) repair and is required for cellular resistance to ionizing radiation (IR) ( 1 , 2 ). (amegroups.org)

and (3) the level of tumor-derived extracellular miRNAs might vary with the age of the patient and the status of disease, so their value as non-invasive biomarkers are reduced. (frontiersin.org)
More than 90% of extracellular miRNAs are vesicle-free, but form a complex with proteins such as Agonaute2 (AGO2) ( 22 , 23 ). (frontiersin.org)
Moreover, we showed that Acanthamoeba produces severe HBMEC cytotoxicity by secreting extracellular proteases, as well as using contact-dependent mechanisms such as phagocytosis ( 12 ), which may play an important role in blood-brain barrier perturbations. (asm.org)

Homo sapiens excision repair cross-complementing rodent repair deficiency, complementation group 3 (ERCC3), mRNA. (dbcls.jp)
Homo sapiens BUB3 mitotic checkpoint protein (BUB3), transcript variant 2, mRNA. (dbcls.jp)
Homo sapiens CGG triplet repeat binding protein 1 (CGGBP1), transcript variant 1, mRNA. (dbcls.jp)

the E-value for the PH_3 domain shown below is 1.3e-46. (embl.de)

Only 1.5% of nucleic acids in human genome are used for protein encoding, but other 98.5% of the genome does not encode proteins. (jcancer.org)

Fig. 3: Mitogen starvation-induced recruitment of PI3KC2-β to LyLEs is mediated by its association with Rab7 and is counteracted by PKN2. (nature.com)

Raw data for results from screening kinase activity towards T279 of PI3KC2-β are provided in Supplementary Table 2 . (nature.com)
Here, we analyzed the protein levels, activity and role of Rsk in in vivo and in vitro HD models. (biomedcentral.com)
Interestingly, previous data from a HD cellular model show a de-regulation of both kinases that control Rsk activity. (biomedcentral.com)
Insulin-stimulated glucose transport in isolated skeletal muscle was reduced 47% in obese versus lean rats, with a parallel 42% reduction in tyrosine-associated PI 3-kinase activity. (diabetesjournals.org)
Thus, deficiency in DNA-PKcs activity results in a severe combined immunodeficiency (SCID) phenotype in mammals ( 3 - 5 ). (amegroups.org)

Another line of research development centers on the establishment of novel chemical libraries aiming at mechanism-based or lead compound-based drug discovery for cancer/inflammation, particularly by targeting Bcl-2 family proteins and apoptosis pathways, transcription factors as well as epigenetic therapy with the aid of molecular docking and chemical synthesis. (utmb.edu)
In terms of its mechanism of action, nicotine slows the progression of PD by inhibiting Sirtuin 6, a stress‑responsive protein deacetylase, thereby decreasing neuronal apoptosis and improving neuronal survival. (spandidos-publications.com)

Figure 3: Deletion of both Akt1 and Akt2 in liver results in hyperglycemia, glucose intolerance and insulin resistance. (nature.com)
Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). (nature.com)
Rab proteins are known to be important participants in insulin secretion by pancreatic β cells. (researchsquare.com)

3. Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine. (jcancer.org)

Anatomy22

Organisms11

Chemicals and Drugs160

Analytical, Diagnostic and Therapeutic Techniques and Equipment14

Phenomena and Processes45

Information Science3

Serine4

Phosphorylation13

PI3K11

PDK18

Activates4

Ribosomal S6 kin1

Receptor tyrosi1

Phosphorylates3

Lipids2

Enzymes3

Downstream1

Abstract2

Inhibitors2

Inhibitor5

Lipid3

Substrate3

PDPK16

Membrane4

Calmodulin-dependent protein1

Glycogen1

Gene4

Regulator1

Inhibition2

Genes5

Catalytic domain1

Activation3

Substrates1

Signaling7

Mutations1

AMPK1

Pathway3

Extracellular3

Homo3

Domain1

Encode1

PKN21

Activity5

Apoptosis2

Insulin3

Cell Biology1