Q9Z2A0 (PDPK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
3-phosphoinositide-dependent protein kinase 1
Short name=mPDK1
EC=2.7.11.1

Gene names

Name:	Pdpk1
Synonyms:	Pdk1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	559 AA.
Sequence status	Complete.
Protein existence	Evidence 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.6 Ref.7 Ref.8 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.6
Subcellular location	Cytoplasm. Nucleus By similarity. Cell membrane; Peripheral membrane protein. Cell junction › focal 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.8
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 process	Transcription Transcription regulation
Cellular component	Cell junction Cell membrane Cytoplasm Membrane Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of protein kinase B activity Inferred from electronic annotation. Source: Compara cellular response to insulin stimulus Inferred from electronic annotation. Source: Compara focal adhesion assembly Inferred from electronic annotation. Source: Compara hyperosmotic response Inferred from direct assay PubMed 12783890. Source: MGI intracellular signal transduction Inferred from electronic annotation. Source: Compara 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: Compara 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: Compara peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of establishment of protein localization to plasma membrane Inferred from electronic annotation. Source: Compara regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara regulation of endothelial cell migration Inferred from mutant phenotype Ref.8. Source: UniProtKB regulation of mast cell degranulation Inferred from mutant phenotype Ref.14. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW signal transduction Traceable author statement Ref.1. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW type B pancreatic cell development Inferred from mutant phenotype Ref.11. Source: UniProtKB
Cellular_component	cytoplasmic membrane-bounded vesicle Inferred from direct assay PubMed 12783890. Source: MGI cytosol Inferred from electronic annotation. Source: Compara 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_function	3-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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 559	559	3-phosphoinositide-dependent protein kinase 1		PRO_0000086501
Regions
	Domain	85 – 345	261	Protein kinase
	Domain	462 – 553	92	PH
	Nucleotide binding	91 – 99	9	ATP By similarity
	Compositional bias	392 – 401	10	Poly-Ser
Sites
	Active site	208	1	Proton acceptor By similarity
	Binding site	114	1	ATP By similarity
Amino acid modifications
	Modified residue	9	1	Phosphotyrosine; by SRC and INSR By similarity
	Modified residue	25	1	Phosphoserine By similarity
	Modified residue	244	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	357	1	Phosphothreonine; by MELK By similarity
	Modified residue	376	1	Phosphotyrosine; by SRC and INSR By similarity
	Modified residue	379	1	Phosphotyrosine; by SRC and INSR By similarity
	Modified residue	396	1	Phosphoserine By similarity
	Modified residue	397	1	Phosphoserine; by MAP3K5 By similarity
	Modified residue	399	1	Phosphoserine By similarity
	Modified residue	401	1	Phosphoserine; by MAP3K5 By similarity
	Modified residue	413	1	Phosphoserine By similarity
	Modified residue	504	1	Phosphoserine; by PKC/PRKCQ Ref.12
	Modified residue	516	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	532	1	Phosphoserine; by PKC/PRKCQ Ref.12
Experimental info
	Sequence conflict	84	1	D → N in AAC67544. Ref.1
	Sequence conflict	248	1	T → P in AAC96115. Ref.3
	Sequence conflict	285	1	F → S in AAC96115. Ref.3
	Sequence conflict	546	1	W → R in AAC96115. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q9Z2A0 [UniParc]. Last modified October 18, 2001. Version 2. Checksum: F2A617A27460FAC9	FASTA	559	63,759
	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

References

	« Hide 'large scale' referencesShow '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]	"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.
[7]	"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.
[8]	"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.
[9]	"Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-244, MASS SPECTROMETRY. Tissue: Brain cortex.
[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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-244, MASS SPECTROMETRY. 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.
+	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.
IPI	IPI00323609.
RefSeq	NP_035192.2. NM_011062.4.
UniGene	Mm.10504.
3D structure databases
ProteinModelPortal	Q9Z2A0.
SMR	Q9Z2A0. Positions 45-552.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Z2A0. 20 interactions.
MINT	MINT-4106940.
STRING	10090.ENSMUSP00000099991.
PTM databases
PhosphoSite	Q9Z2A0.
Proteomic databases
PaxDb	Q9Z2A0.
PRIDE	Q9Z2A0.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000102927; ENSMUSP00000099991; ENSMUSG00000024122.
GeneID	18607.
KEGG	mmu:18607.
UCSC	uc008auk.2. mouse.
Organism-specific databases
CTD	5170.
MGI	MGI:1338068. Pdpk1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00550000074819.
HOGENOM	HOG000233026.
HOVERGEN	HBG098357.
InParanoid	A6H6U3.
KO	K06276.
OMA	HLQTPPK.
OrthoDB	EOG4ZPDVM.
Enzyme and pathway databases
BRENDA	2.7.11.1. 3474.
Gene expression databases
ArrayExpress	Q9Z2A0.
Bgee	Q9Z2A0.
CleanEx	MM_PDK1. MM_PDPK1.
Genevestigator	Q9Z2A0.
GermOnline	ENSMUSG00000024122. Mus musculus.
Family and domain databases
Gene3D	2.30.29.30. 2 hits.
InterPro	IPR011009. Kinase-like_dom. IPR011993. PH_like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50003. PH_DOMAIN. False negative. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	PDPK1. mouse.
NextBio	294526.
SOURCE	Search...

Entry information

Entry name

PDPK1_MOUSE

Accession

Primary (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:	May 29, 2013
This is version 119 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program