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Protein

3-phosphoinositide-dependent protein kinase 1

Gene

Pdpk1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca2+ entry and Ca2+-activated K+ channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages (By similarity).By similarity1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-376 and Tyr-379 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-244 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei114ATPBy similarity1
Binding sitei169ATPBy similarity1
Active sitei208Proton acceptorPROSITE-ProRule annotation1
Binding sitei212ATP; via carbonyl oxygenBy similarity1
Binding sitei226ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi95 – 97ATPBy similarity3
Nucleotide bindingi163 – 165ATPBy similarity3

GO - Molecular functioni

  • 3-phosphoinositide-dependent protein kinase activity Source: RGD
  • ATP binding Source: UniProtKB-KW
  • insulin receptor binding Source: RGD
  • phospholipase activator activity Source: Ensembl
  • protein kinase binding Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1. 5301.
ReactomeiR-RNO-114604. GPVI-mediated activation cascade.
R-RNO-1257604. PIP3 activates AKT signaling.
R-RNO-165158. Activation of AKT2.
R-RNO-202424. Downstream TCR signaling.
R-RNO-2730905. Role of LAT2/NTAL/LAB on calcium mobilization.
R-RNO-354192. Integrin alphaIIb beta3 signaling.
R-RNO-389357. CD28 dependent PI3K/Akt signaling.
R-RNO-389513. CTLA4 inhibitory signaling.
R-RNO-392451. G beta:gamma signalling through PI3Kgamma.
R-RNO-444257. RSK activation.
R-RNO-5218920. VEGFR2 mediated vascular permeability.
R-RNO-5218921. VEGFR2 mediated cell proliferation.
R-RNO-5625740. RHO GTPases activate PKNs.
R-RNO-6804757. Regulation of TP53 Degradation.

Names & Taxonomyi

Protein namesi
Recommended name:
3-phosphoinositide-dependent protein kinase 1 (EC:2.7.11.1)
Alternative name(s):
Protein kinase B kinase
Short name:
PkB kinase
Gene namesi
Name:Pdpk1
Synonyms:Pdk1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 10

Organism-specific databases

RGDi620307. Pdpk1.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity
  • Cell membrane By similarity; Peripheral membrane protein By similarity
  • Cell junctionfocal adhesion By similarity

  • Note: Tyrosine phosphorylation seems to occur only at the cell membrane. Translocates to the cell membrane following insulin stimulation by a mechanism that involves binding to GRB14 and INSR. SRC and HSP90 promote its localization to the cell membrane. Its nuclear localization is dependent on its association with PTPN6 and its phosphorylation at Ser-396. Restricted to the nucleus in neuronal cells while in non-neuronal cells it is found in the cytoplasm. The Ser-244 phosphorylated form is distributed along the perinuclear region in neuronal cells while in non-neuronal cells it is found in both the nucleus and the cytoplasm. IGF1 transiently increases phosphorylation at Ser-244 of neuronal PDPK1, resulting in its translocation to other cellular compartments. The tyrosine-phosphorylated form colocalizes with PTK2B in focal adhesions after angiotensin II stimulation (By similarity).By similarity

GO - Cellular componenti

  • cell projection Source: Ensembl
  • cytoplasmic, membrane-bounded vesicle Source: Ensembl
  • cytosol Source: RGD
  • focal adhesion Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB-SubCell
  • perikaryon Source: RGD
  • plasma membrane Source: RGD
  • postsynaptic density Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Cytoplasm, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000865021 – 5593-phosphoinositide-dependent protein kinase 1Add BLAST559

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei9Phosphotyrosine; by SRC and INSRBy similarity1
Modified residuei25PhosphoserineBy similarity1
Modified residuei244PhosphoserineCombined sources1
Modified residuei307N6-acetyllysineBy similarity1
Modified residuei357Phosphothreonine; by MELKBy similarity1
Modified residuei376Phosphotyrosine; by SRC and INSRBy similarity1
Modified residuei379Phosphotyrosine; by SRC and INSRBy similarity1
Modified residuei396PhosphoserineBy similarity1
Modified residuei397Phosphoserine; by MAP3K5By similarity1
Modified residuei399PhosphoserineBy similarity1
Modified residuei401Phosphoserine; by MAP3K5By similarity1
Modified residuei413PhosphoserineBy similarity1
Modified residuei504Phosphoserine; by PKC/PRKCQBy similarity1
Modified residuei516Phosphothreonine; by autocatalysisBy similarity1
Modified residuei532Phosphoserine; by PKC/PRKCQBy similarity1

Post-translational modificationi

Phosphorylation on Ser-244 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-244, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2. Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-376 and Tyr-379 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-244 and palmitate-induced phosphorylation at Ser-532 and Ser-504 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-357 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-397 and Ser-401 by MAP3K5 (By similarity).By similarity
Monoubiquitinated in the kinase domain, deubiquitinated by USP4.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiO55173.
PRIDEiO55173.

PTM databases

iPTMnetiO55173.
PhosphoSitePlusiO55173.

Expressioni

Gene expression databases

BgeeiENSRNOG00000006136.
GenevisibleiO55173. RN.

Interactioni

Subunit structurei

Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-244 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7 (By similarity). Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.By similarity1 Publication

GO - Molecular functioni

  • insulin receptor binding Source: RGD
  • protein kinase binding Source: RGD

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000061683.

Structurei

3D structure databases

ProteinModelPortaliO55173.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini85 – 345Protein kinasePROSITE-ProRule annotationAdd BLAST261
Domaini462 – 553PHAdd BLAST92

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni116 – 160PIF-pocketBy similarityAdd BLAST45

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi392 – 399Poly-Ser8

Domaini

The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.By similarity
The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.By similarity

Sequence similaritiesi

Contains 1 PH domain.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0592. Eukaryota.
ENOG410XRT8. LUCA.
GeneTreeiENSGT00550000074819.
HOGENOMiHOG000233026.
HOVERGENiHBG098357.
InParanoidiO55173.
KOiK06276.
OMAiSGNADRW.
OrthoDBiEOG091G06CX.
TreeFamiTF105423.

Family and domain databases

CDDicd01262. PH_PDK1. 1 hit.
Gene3Di2.30.29.30. 2 hits.
InterProiIPR011009. Kinase-like_dom.
IPR033931. PDK1-typ_PH.
IPR011993. PH_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF14593. PH_3. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O55173-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MARTTSQLYD AVPIQSSVVL CSCPSPSMVR SQTEPSSSPG IPSGVSRQGS
60 70 80 90 100
TMDGTTAEAR PSTNPLQQHP AQLPPQPRKK RPEDFKFGKI LGEGSFSTVV
110 120 130 140 150
LARELATSRE YAIKILEKRH IIKENKVPYV TRERDVMSRL DHPFFVKLYF
160 170 180 190 200
TFQDDEKLYF GLSYAKNGEL LKYIRKIGSF DETCTRFYTA EIVSALEYLH
210 220 230 240 250
GKGIIHRDLK PENILLNEDM HIQITDFGTA KVLSPDSKQA RANSFVGTAQ
260 270 280 290 300
YVSPELLTEK SACKSSDLWA LGCIIYQLVA GLPPFRAGNE YLIFQKIIKL
310 320 330 340 350
EYDFPEKFFP KARDLVEKLL VLDATKRLGC EEMEGYGPLK AHPFFESITW
360 370 380 390 400
ENLHQQTPPK LTAYLPAMSE DDEDCYGNYD NLLSQFGCMQ VSSSSSSHSL
410 420 430 440 450
SAVDASLPQR SGSNIEQYIH DLDTNSFELD LQFSEDEKRL LLEKQAGGNP
460 470 480 490 500
WHQFVENNLI LKMGPVDKRK GLFARRRQLL LTEGPHLYYV DPVNKVLKGE
510 520 530 540 550
IPWSQELRPE AKNFKTFFVH TPNRTYYLMD PSGNAHKWCR KIQEVWRQQY

QSSPDAAVQ
Length:559
Mass (Da):63,593
Last modified:July 11, 2012 - v2
Checksum:i4D06A17F769B800F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti401S → C in CAA75758 (PubMed:9445477).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y15748 mRNA. Translation: CAA75758.1.
CH473948 Genomic DNA. Translation: EDM03805.1.
RefSeqiNP_112343.1. NM_031081.1.
UniGeneiRn.10905.

Genome annotation databases

EnsembliENSRNOT00000067660; ENSRNOP00000061683; ENSRNOG00000006136.
GeneIDi81745.
KEGGirno:81745.
UCSCiRGD:620307. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y15748 mRNA. Translation: CAA75758.1.
CH473948 Genomic DNA. Translation: EDM03805.1.
RefSeqiNP_112343.1. NM_031081.1.
UniGeneiRn.10905.

3D structure databases

ProteinModelPortaliO55173.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000061683.

PTM databases

iPTMnetiO55173.
PhosphoSitePlusiO55173.

Proteomic databases

PaxDbiO55173.
PRIDEiO55173.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000067660; ENSRNOP00000061683; ENSRNOG00000006136.
GeneIDi81745.
KEGGirno:81745.
UCSCiRGD:620307. rat.

Organism-specific databases

CTDi5170.
RGDi620307. Pdpk1.

Phylogenomic databases

eggNOGiKOG0592. Eukaryota.
ENOG410XRT8. LUCA.
GeneTreeiENSGT00550000074819.
HOGENOMiHOG000233026.
HOVERGENiHBG098357.
InParanoidiO55173.
KOiK06276.
OMAiSGNADRW.
OrthoDBiEOG091G06CX.
TreeFamiTF105423.

Enzyme and pathway databases

BRENDAi2.7.11.1. 5301.
ReactomeiR-RNO-114604. GPVI-mediated activation cascade.
R-RNO-1257604. PIP3 activates AKT signaling.
R-RNO-165158. Activation of AKT2.
R-RNO-202424. Downstream TCR signaling.
R-RNO-2730905. Role of LAT2/NTAL/LAB on calcium mobilization.
R-RNO-354192. Integrin alphaIIb beta3 signaling.
R-RNO-389357. CD28 dependent PI3K/Akt signaling.
R-RNO-389513. CTLA4 inhibitory signaling.
R-RNO-392451. G beta:gamma signalling through PI3Kgamma.
R-RNO-444257. RSK activation.
R-RNO-5218920. VEGFR2 mediated vascular permeability.
R-RNO-5218921. VEGFR2 mediated cell proliferation.
R-RNO-5625740. RHO GTPases activate PKNs.
R-RNO-6804757. Regulation of TP53 Degradation.

Miscellaneous databases

PROiO55173.

Gene expression databases

BgeeiENSRNOG00000006136.
GenevisibleiO55173. RN.

Family and domain databases

CDDicd01262. PH_PDK1. 1 hit.
Gene3Di2.30.29.30. 2 hits.
InterProiIPR011009. Kinase-like_dom.
IPR033931. PDK1-typ_PH.
IPR011993. PH_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF14593. PH_3. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 2 hits.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiPDPK1_RAT
AccessioniPrimary (citable) accession number: O55173
Secondary accession number(s): G3V9W3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 18, 2001
Last sequence update: July 11, 2012
Last modified: November 30, 2016
This is version 138 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.