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Q9Z2A0 (PDPK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
3-phosphoinositide-dependent protein kinase 1

Short name=mPDK1
EC=2.7.11.1
Gene names
Name:Pdpk1
Synonyms:Pdk1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length559 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.5 Ref.7 Ref.8 Ref.9 Ref.11 Ref.13 Ref.14 Ref.15

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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.

Subunit structure

Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PAK1, PTK2B, GRB14, 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. 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 similarity. Interacts with PKN1 (via C-terminus) and PPARG. Ref.5 Ref.7

Subcellular location

Cytoplasm. Nucleus By similarity. Cell membrane; Peripheral membrane protein. 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-241 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. Ref.9

Tissue specificity

Highly expressed in heart, brain, liver and testis, also expressed in embryonic cells.

Domain

The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization By similarity.

Post-translational modification

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 By similarity. 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. Ref.12

Monoubiquitinated in the kinase domain, deubiquitinated by USP4 By similarity.

Disruption phenotype

Mice show severe pancreatic hypoplasia at birth and ensuing hyperglycemia at postnatal stages and die of heart failure by 11 weeks of age. Ref.11 Ref.13

Sequence similarities

Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily.

Contains 1 PH domain.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCell junction
Cell membrane
Cytoplasm
Membrane
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of protein kinase B activity

Inferred from electronic annotation. Source: Ensembl

cellular response to insulin stimulus

Inferred from electronic annotation. Source: Ensembl

extrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

focal adhesion assembly

Inferred from electronic annotation. Source: Ensembl

hyperosmotic response

Inferred from direct assay PubMed 12783890. Source: MGI

intracellular signal transduction

Inferred from electronic annotation. Source: Ensembl

negative regulation of cardiac muscle cell apoptotic process

Inferred from mutant phenotype Ref.13. Source: UniProtKB

negative regulation of protein kinase activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of toll-like receptor signaling pathway

Inferred from mutant phenotype Ref.15. Source: UniProtKB

negative regulation of transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

peptidyl-threonine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of establishment of protein localization to plasma membrane

Inferred from electronic annotation. Source: Ensembl

regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

regulation of endothelial cell migration

Inferred from mutant phenotype Ref.9. Source: UniProtKB

regulation of mast cell degranulation

Inferred from mutant phenotype Ref.14. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

signal transduction

Traceable author statement Ref.1. Source: MGI

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

type B pancreatic cell development

Inferred from mutant phenotype Ref.11. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 12783890. Source: MGI

cytoplasmic membrane-bounded vesicle

Inferred from direct assay PubMed 12783890. Source: MGI

cytosol

Inferred from electronic annotation. Source: Ensembl

focal adhesion

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_function3-phosphoinositide-dependent protein kinase activity

Inferred from direct assay Ref.1. Source: MGI

ATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 5595593-phosphoinositide-dependent protein kinase 1
PRO_0000086501

Regions

Domain85 – 345261Protein kinase
Domain462 – 55392PH
Nucleotide binding91 – 999ATP By similarity
Compositional bias392 – 40110Poly-Ser

Sites

Active site2081Proton acceptor By similarity
Binding site1141ATP By similarity

Amino acid modifications

Modified residue91Phosphotyrosine; by SRC and INSR By similarity
Modified residue251Phosphoserine By similarity
Modified residue2441Phosphoserine; alternate Ref.6
Modified residue2441Phosphoserine; by autocatalysis; alternate By similarity
Modified residue3071N6-acetyllysine Ref.16
Modified residue3571Phosphothreonine; by MELK By similarity
Modified residue3761Phosphotyrosine; by SRC and INSR By similarity
Modified residue3791Phosphotyrosine; by SRC and INSR By similarity
Modified residue3961Phosphoserine By similarity
Modified residue3971Phosphoserine; by MAP3K5 By similarity
Modified residue3991Phosphoserine By similarity
Modified residue4011Phosphoserine; by MAP3K5 By similarity
Modified residue4131Phosphoserine By similarity
Modified residue5041Phosphoserine; by PKC/PRKCQ Ref.12
Modified residue5161Phosphothreonine; by autocatalysis By similarity
Modified residue5321Phosphoserine; by PKC/PRKCQ Ref.12

Experimental info

Sequence conflict841D → N in AAC67544. Ref.1
Sequence conflict2481T → P in AAC96115. Ref.3
Sequence conflict2851F → S in AAC96115. Ref.3
Sequence conflict5461W → R in AAC96115. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q9Z2A0 [UniParc].

Last modified October 18, 2001. Version 2.
Checksum: F2A617A27460FAC9

FASTA55963,759
        10         20         30         40         50         60 
MARTTSQLYD AVPIQSSVVL CSCPSPSMVR SQTEPGSSPG IPSGVSRQGS TMDGTTAEAR 

        70         80         90        100        110        120 
PSTNPLQQHP AQLPPQPRKK RPEDFKFGKI LGEGSFSTVV LARELATSRE YAIKILEKRH 

       130        140        150        160        170        180 
IIKENKVPYV TRERDVMSRL DHPFFVKLYF TFQDDEKLYF GLSYAKNGEL LKYIRKIGSF 

       190        200        210        220        230        240 
DETCTRFYTA EIVSALEYLH GKGIIHRDLK PENILLNEDM HIQITDFGTA KVLSPESKQA 

       250        260        270        280        290        300 
RANSFVGTAQ YVSPELLTEK SACKSSDLWA LGCIIYQLVA GLPPFRAGNE YLIFQKIIKL 

       310        320        330        340        350        360 
EYHFPEKFFP KARDLVEKLL VLDATKRLGC EEMEGYGPLK AHPFFETITW ENLHQQTPPK 

       370        380        390        400        410        420 
LTAYLPAMSE DDEDCYGNYD NLLSQFGFMQ VSSSSSSHSL STVETSLPQR SGSNIEQYIH 

       430        440        450        460        470        480 
DLDTNSFELD LQFSEDEKRL LLEKQAGGNP WHQFVENNLI LKMGPVDKRK GLFARRRQLL 

       490        500        510        520        530        540 
LTEGPHLYYV DPVNKVLKGE IPWSQELRPE AKNFKTFFVH TPNRTYYLMD PSGNAHKWCR 

       550 
KIQEVWRQQY QSNPDAAVQ 

« Hide

References

« Hide 'large scale' references
[1]"Primary structure, tissue distribution, and expression of mouse phosphoinositide-dependent protein kinase-1, a protein kinase that phosphorylates and activates protein kinase C zeta."
Dong L.Q., Zhang R.-B., Langlais P., He H., Clark M., Zhu L., Liu F.
J. Biol. Chem. 274:8117-8122(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Liver.
[2]"Mouse phosphoinositide-dependent protein kinase 1 (mPDK1)."
Park J., Hemmings B.A.
Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[3]Xu P., Taylor S.
Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[5]"Phosphorylation of protein kinase N by phosphoinositide-dependent protein kinase-1 mediates insulin signals to the actin cytoskeleton."
Dong L.Q., Landa L.R., Wick M.J., Zhu L., Mukai H., Ono Y., Liu F.
Proc. Natl. Acad. Sci. U.S.A. 97:5089-5094(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF PKN1 AND PKN2, INTERACTION WITH PKN1 AND PKN2.
[6]"Phosphoproteomic analysis of the developing mouse brain."
Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.
Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-244, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic brain.
[7]"3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation."
Yin Y., Yuan H., Wang C., Pattabiraman N., Rao M., Pestell R.G., Glazer R.I.
Mol. Endocrinol. 20:268-278(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PPARG.
[8]"Notch-induced T cell development requires phosphoinositide-dependent kinase 1."
Kelly A.P., Finlay D.K., Hinton H.J., Clarke R.G., Fiorini E., Radtke F., Cantrell D.A.
EMBO J. 26:3441-3450(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Essential role of PDK1 in regulating endothelial cell migration."
Primo L., di Blasio L., Roca C., Droetto S., Piva R., Schaffhausen B., Bussolino F.
J. Cell Biol. 176:1035-1047(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[11]"Pdk1 activity controls proliferation, survival, and growth of developing pancreatic cells."
Westmoreland J.J., Wang Q., Bouzaffour M., Baker S.J., Sosa-Pineda B.
Dev. Biol. 334:285-298(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[12]"Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance."
Wang C., Liu M., Riojas R.A., Xin X., Gao Z., Zeng R., Wu J., Dong L.Q., Liu F.
J. Biol. Chem. 284:2038-2044(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-504 AND SER-532 BY PKC/PRKCQ.
[13]"PDK1 coordinates survival pathways and beta-adrenergic response in the heart."
Ito K., Akazawa H., Tamagawa M., Furukawa K., Ogawa W., Yasuda N., Kudo Y., Liao C.H., Yamamoto R., Sato T., Molkentin J.D., Kasuga M., Noda T., Nakaya H., Komuro I.
Proc. Natl. Acad. Sci. U.S.A. 106:8689-8694(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[14]"Phosphoinositide-dependent kinase PDK1 in the regulation of Ca2+ entry into mast cells."
Shumilina E., Zemtsova I.M., Heise N., Schmid E., Eichenmueller M., Tyan L., Rexhepaj R., Lang F.
Cell. Physiol. Biochem. 26:699-706(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[15]"Phosphoinositide-dependent kinase 1 provides negative feedback inhibition to Toll-like receptor-mediated NF-kappaB activation in macrophages."
Chaurasia B., Mauer J., Koch L., Goldau J., Kock A.S., Bruening J.C.
Mol. Cell. Biol. 30:4354-4366(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[16]"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-307, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic fibroblast.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF086625 mRNA. Translation: AAC67544.1.
AF126294 mRNA. Translation: AAD38505.1.
AF079535 mRNA. Translation: AAC96115.1.
BC146001 mRNA. Translation: AAI46002.1.
BC146003 mRNA. Translation: AAI46004.1.
CCDSCCDS28474.1.
RefSeqNP_035192.2. NM_011062.4.
UniGeneMm.10504.

3D structure databases

ProteinModelPortalQ9Z2A0.
SMRQ9Z2A0. Positions 45-552.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid202099. 1 interaction.
IntActQ9Z2A0. 21 interactions.
MINTMINT-4106940.
STRING10090.ENSMUSP00000099991.

PTM databases

PhosphoSiteQ9Z2A0.

Proteomic databases

MaxQBQ9Z2A0.
PaxDbQ9Z2A0.
PRIDEQ9Z2A0.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000102927; ENSMUSP00000099991; ENSMUSG00000024122.
GeneID18607.
KEGGmmu:18607.
UCSCuc008auk.2. mouse.

Organism-specific databases

CTD5170.
MGIMGI:1338068. Pdpk1.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00550000074819.
HOGENOMHOG000233026.
HOVERGENHBG098357.
InParanoidA6H6U3.
KOK06276.
OMASEDMHIQ.
OrthoDBEOG7R56S4.
PhylomeDBQ9Z2A0.
TreeFamTF105423.

Enzyme and pathway databases

BRENDA2.7.11.1. 3474.

Gene expression databases

ArrayExpressQ9Z2A0.
BgeeQ9Z2A0.
CleanExMM_PDK1.
MM_PDPK1.
GenevestigatorQ9Z2A0.

Family and domain databases

Gene3D2.30.29.30. 2 hits.
InterProIPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPDPK1. mouse.
NextBio294526.
PROQ9Z2A0.
SOURCESearch...

Entry information

Entry namePDPK1_MOUSE
AccessionPrimary (citable) accession number: Q9Z2A0
Secondary accession number(s): A6H6U3, Q9R1D8, Q9R215
Entry history
Integrated into UniProtKB/Swiss-Prot: October 18, 2001
Last sequence update: October 18, 2001
Last modified: July 9, 2014
This is version 129 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot