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3-phosphoinositide-dependent protein kinase 1 (hPDK1) (EC 2.7.11.1)

 PDPK1_HUMAN             Reviewed;         556 AA.
O15530; H0Y4Z0; Q59EH6; Q6FI20; Q8IV52; Q9BRD5;
18-OCT-2001, integrated into UniProtKB/Swiss-Prot.
01-JAN-1998, sequence version 1.
18-JUL-2018, entry version 210.
RecName: Full=3-phosphoinositide-dependent protein kinase 1;
Short=hPDK1;
EC=2.7.11.1;
Name=PDPK1; Synonyms=PDK1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN
PHOSPHORYLATION OF PKB/AKT1.
PubMed=9094314; DOI=10.1016/S0960-9822(06)00122-9;
Alessi D.R., James S.R., Downes C.P., Holmes A.B., Gaffney P.R.J.,
Reese C.B., Cohen P.;
"Characterization of a 3-phosphoinositide-dependent protein kinase
which phosphorylates and activates protein kinase B alpha.";
Curr. Biol. 7:261-269(1997).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=9368760; DOI=10.1016/S0960-9822(06)00336-8;
Alessi D.R., Deak M., Casamayor A., Caudwell F.B., Morrice N.A.,
Norman D.G., Gaffney P.R.J., Reese C.B., MacDougall C.N., Harbison D.,
Ashworth A., Bownes M.;
"3-phosphoinositide-dependent protein kinase-1 (PDK1): structural and
functional homology with the Drosophila DSTPK61 kinase.";
Curr. Biol. 7:776-789(1997).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
TISSUE=Myeloid;
PubMed=9445477; DOI=10.1126/science.279.5351.710;
Stephens L.R., Anderson K.E., Stokoe D., Erdjument-Bromage H.,
Painter G.F., Holmes A.B., Gaffney P.R.J., Reese C.B., McCormick F.,
Tempst P., Coadwell W.J., Hawkins P.T.;
"Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-
trisphosphate-dependent activation of protein kinase B.";
Science 279:710-714(1998).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
"Cloning of human full open reading frames in Gateway(TM) system entry
vector (pDONR201).";
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
TISSUE=Brain;
Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
Ohara O., Nagase T., Kikuno R.F.;
"Homo sapiens protein coding cDNA.";
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15616553; DOI=10.1038/nature03187;
Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
Rubin E.M., Pennacchio L.A.;
"The sequence and analysis of duplication-rich human chromosome 16.";
Nature 432:988-994(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
TISSUE=Brain, Kidney, and Uterus;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[8]
PROTEIN SEQUENCE OF 60-75; 87-100; 184-199; 239-257 AND 284-293,
PHOSPHORYLATION AT SER-241, AND IDENTIFICATION BY MASS SPECTROMETRY.
TISSUE=Embryonic kidney;
Bienvenut W.V., Waridel P., Quadroni M.;
Submitted (MAR-2009) to UniProtKB.
[9]
MUTAGENESIS OF ARG-474, AND ALTERNATIVE SPLICING.
PubMed=9637919; DOI=10.1016/S0960-9822(98)70274-X;
Anderson K.E., Coadwell W.J., Stephens L.R., Hawkins P.T.;
"Translocation of PDK-1 to the plasma membrane is important in
allowing PDK-1 to activate protein kinase B.";
Curr. Biol. 8:684-691(1998).
[10]
FUNCTION IN PHOSPHORYLATION OF PRKCZ.
PubMed=9768361; DOI=10.1016/S0960-9822(98)70444-0;
Chou M.M., Hou W., Johnson J., Graham L.K., Lee M.H., Chen C.S.,
Newton A.C., Schaffhausen B.S., Toker A.;
"Regulation of protein kinase C zeta by PI 3-kinase and PDK-1.";
Curr. Biol. 8:1069-1077(1998).
[11]
FUNCTION IN PHOSPHORYLATION OF PRKACA.
PubMed=9707564; DOI=10.1073/pnas.95.17.9849;
Cheng X., Ma Y., Moore M., Hemmings B.A., Taylor S.S.;
"Phosphorylation and activation of cAMP-dependent protein kinase by
phosphoinositide-dependent protein kinase.";
Proc. Natl. Acad. Sci. U.S.A. 95:9849-9854(1998).
[12]
FUNCTION IN PHOSPHORYLATION OF RPS6KB1.
PubMed=9445476; DOI=10.1126/science.279.5351.707;
Pullen N., Dennis P.B., Andjelkovic M., Dufner A., Kozma S.C.,
Hemmings B.A., Thomas G.;
"Phosphorylation and activation of p70s6k by PDK1.";
Science 279:707-710(1998).
[13]
PHOSPHORYLATION AT SER-25; SER-241; SER-393; SER-396 AND SER-410, AND
MUTAGENESIS OF SER-25; SER-241; SER-393; SER-396 AND SER-410.
PubMed=10455013; DOI=10.1042/bj3420287;
Casamayor A., Morrice N.A., Alessi D.R.;
"Phosphorylation of Ser-241 is essential for the activity of 3-
phosphoinositide-dependent protein kinase-1: identification of five
sites of phosphorylation in vivo.";
Biochem. J. 342:287-292(1999).
[14]
MUTAGENESIS OF ALA-277.
PubMed=10364160; DOI=10.1101/gad.13.11.1438;
Paradis S., Ailion M., Toker A., Thomas J.H., Ruvkun G.;
"A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3
kinase signals that regulate diapause in Caenorhabditis elegans.";
Genes Dev. 13:1438-1452(1999).
[15]
FUNCTION IN PHOSPHORYLATION OF RPS6KA3.
PubMed=10480933; DOI=10.1074/jbc.274.38.27168;
Jensen C.J., Buch M.-B., Krag T.O., Hemmings B.A., Gammeltoft S.,
Froedin M.;
"90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-
phosphoinositide-dependent protein kinase-1.";
J. Biol. Chem. 274:27168-27176(1999).
[16]
FUNCTION IN PHOSPHORYLATION OF PAK1, AND INTERACTION WITH PAK1.
PubMed=10995762; DOI=10.1074/jbc.M006553200;
King C.C., Gardiner E.M., Zenke F.T., Bohl B.P., Newton A.C.,
Hemmings B.A., Bokoch G.M.;
"p21-activated kinase (PAK1) is phosphorylated and activated by 3-
phosphoinositide-dependent kinase-1 (PDK1).";
J. Biol. Chem. 275:41201-41209(2000).
[17]
PHOSPHORYLATION AT TYR-9; SER-241; TYR-373 AND TYR-376, AND
MUTAGENESIS OF TYR-9; TYR-373 AND TYR-376.
PubMed=11481331; DOI=10.1074/jbc.M105916200;
Park J., Hill M.M., Hess D., Brazil D.P., Hofsteenge J.,
Hemmings B.A.;
"Identification of tyrosine phosphorylation sites on 3-
phosphoinositide-dependent protein kinase-1 (PDK1) and their role in
regulating kinase activity.";
J. Biol. Chem. 276:37459-37471(2001).
[18]
ENZYME REGULATION, AND INTERACTION WITH YWHAH AND YWHAQ.
PubMed=12177059; DOI=10.1074/jbc.M205141200;
Sato S., Fujita N., Tsuruo T.;
"Regulation of kinase activity of 3-phosphoinositide-dependent protein
kinase-1 by binding to 14-3-3.";
J. Biol. Chem. 277:39360-39367(2002).
[19]
FUNCTION IN PHOSPHORYLATION OF PKB/AKT1.
PubMed=12167717; DOI=10.1128/MCB.22.17.6247-6260.2002;
Scheid M.P., Marignani P.A., Woodgett J.R.;
"Multiple phosphoinositide 3-kinase-dependent steps in activation of
protein kinase B.";
Mol. Cell. Biol. 22:6247-6260(2002).
[20]
FUNCTION, PHOSPHORYLATION AT TYR-9; TYR-373 AND TYR-376 BY SRC,
INTERACTION WITH PTK2B, AND SUBCELLULAR LOCATION.
PubMed=14585963; DOI=10.1128/MCB.23.22.8019-8029.2003;
Taniyama Y., Weber D.S., Rocic P., Hilenski L., Akers M.L., Park J.,
Hemmings B.A., Alexander R.W., Griendling K.K.;
"Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates
focal adhesions.";
Mol. Cell. Biol. 23:8019-8029(2003).
[21]
FUNCTION IN PHOSPHORYLATION OF SGK3, AND INTERACTION WITH SGK3.
PubMed=14604990; DOI=10.1074/jbc.M309653200;
Nilsen T., Slagsvold T., Skjerpen C.S., Brech A., Stenmark H.,
Olsnes S.;
"Peroxisomal targeting as a tool for assaying protein-protein
interactions in the living cell: cytokine-independent survival kinase
(CISK) binds PDK-1 in vivo in a phosphorylation-dependent manner.";
J. Biol. Chem. 279:4794-4801(2004).
[22]
SUBCELLULAR LOCATION, AND INTERACTION WITH GRB14.
PubMed=15210700; DOI=10.1074/jbc.M405340200;
King C.C., Newton A.C.;
"The adaptor protein Grb14 regulates the localization of 3-
phosphoinositide-dependent kinase-1.";
J. Biol. Chem. 279:37518-37527(2004).
[23]
FUNCTION IN PHOSPHORYLATION OF AKT1, AND INTERACTION WITH PKN2.
PubMed=10226025; DOI=10.1016/S0960-9822(99)80186-9;
Balendran A., Casamayor A., Deak M., Paterson A., Gaffney P.,
Currie R., Downes C.P., Alessi D.R.;
"PDK1 acquires PDK2 activity in the presence of a synthetic peptide
derived from the carboxyl terminus of PRK2.";
Curr. Biol. 9:393-404(1999).
[24]
REVIEW ON FUNCTION.
PubMed=15209375; DOI=10.1016/j.semcdb.2003.12.022;
Mora A., Komander D., van Aalten D.M., Alessi D.R.;
"PDK1, the master regulator of AGC kinase signal transduction.";
Semin. Cell Dev. Biol. 15:161-170(2004).
[25]
FUNCTION IN PHOSPHORYLATION OF IKKB, AND INTERACTION WITH IKKB.
PubMed=16207722; DOI=10.1074/jbc.M506235200;
Tanaka H., Fujita N., Tsuruo T.;
"3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase
beta (IkkB) phosphorylation activates NF-kappaB signaling.";
J. Biol. Chem. 280:40965-40973(2005).
[26]
FUNCTION, ENZYME REGULATION, AND INTERACTION WITH STRAP.
PubMed=16251192; DOI=10.1074/jbc.M507539200;
Seong H.A., Jung H., Choi H.S., Kim K.T., Ha H.;
"Regulation of transforming growth factor-beta signaling and PDK1
kinase activity by physical interaction between PDK1 and serine-
threonine kinase receptor-associated protein.";
J. Biol. Chem. 280:42897-42908(2005).
[27]
PHOSPHORYLATION AT SER-396, AND SUBCELLULAR LOCATION.
PubMed=15743829; DOI=10.1128/MCB.25.6.2347-2363.2005;
Scheid M.P., Parsons M., Woodgett J.R.;
"Phosphoinositide-dependent phosphorylation of PDK1 regulates nuclear
translocation.";
Mol. Cell. Biol. 25:2347-2363(2005).
[28]
PHOSPHORYLATION AT TYR-9; TYR-373 AND TYR-376 BY INSR, AND INTERACTION
WITH INSR.
PubMed=16314505; DOI=10.1128/MCB.25.24.10803-10814.2005;
Fiory F., Alberobello A.T., Miele C., Oriente F., Esposito I.,
Corbo V., Ruvo M., Tizzano B., Rasmussen T.E., Gammeltoft S.,
Formisano P., Beguinot F.;
"Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by
the insulin receptor is necessary for insulin metabolic signaling.";
Mol. Cell. Biol. 25:10803-10814(2005).
[29]
PHOSPHORYLATION AT SER-241 AND THR-513.
PubMed=16780920; DOI=10.1016/j.bioorg.2006.05.002;
Gao X., Harris T.K.;
"Role of the PH domain in regulating in vitro autophosphorylation
events required for reconstitution of PDK1 catalytic activity.";
Bioorg. Chem. 34:200-223(2006).
[30]
FUNCTION, AND INTERACTION WITH SMAD2; SMAD3; SMAD4 AND SMAD7.
PubMed=17327236; DOI=10.1074/jbc.M609279200;
Seong H.A., Jung H., Kim K.T., Ha H.;
"3-Phosphoinositide-dependent PDK1 negatively regulates transforming
growth factor-beta-induced signaling in a kinase-dependent manner
through physical interaction with Smad proteins.";
J. Biol. Chem. 282:12272-12289(2007).
[31]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=17371830; DOI=10.1083/jcb.200607053;
Primo L., di Blasio L., Roca C., Droetto S., Piva R., Schaffhausen B.,
Bussolino F.;
"Essential role of PDK1 in regulating endothelial cell migration.";
J. Cell Biol. 176:1035-1047(2007).
[32]
FUNCTION IN PHOSPHORYLATION OF PKN2.
PubMed=18835241; DOI=10.1016/j.abb.2008.09.008;
Lim W.G., Chen X., Liu J.P., Tan B.J., Zhou S., Smith A., Lees N.,
Hou L., Gu F., Yu X.Y., Du Y., Smith D., Verma C., Liu K., Duan W.;
"The C-terminus of PRK2/PKNgamma is required for optimal activation by
RhoA in a GTP-dependent manner.";
Arch. Biochem. Biophys. 479:170-178(2008).
[33]
INTERACTION WITH NPRL2, AND ENZYME REGULATION.
PubMed=18616680; DOI=10.1111/j.1349-7006.2008.00874.x;
Kurata A., Katayama R., Watanabe T., Tsuruo T., Fujita N.;
"TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine
phosphorylation and its downstream signaling.";
Cancer Sci. 99:1827-1834(2008).
[34]
REVIEW ON FUNCTION.
PubMed=18802401; DOI=10.4161/cc.7.19.6810;
Bayascas J.R.;
"Dissecting the role of the 3-phosphoinositide-dependent protein
kinase-1 (PDK1) signalling pathways.";
Cell Cycle 7:2978-2982(2008).
[35]
INTERACTION WITH SRC; RASA1 AND CRK, SUBCELLULAR LOCATION, AND TISSUE
SPECIFICITY.
PubMed=18024423; DOI=10.1074/jbc.M706361200;
Yang K.J., Shin S., Piao L., Shin E., Li Y., Park K.A., Byun H.S.,
Won M., Hong J., Kweon G.R., Hur G.M., Seok J.H., Chun T.,
Brazil D.P., Hemmings B.A., Park J.;
"Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by
Src involves tyrosine phosphorylation of PDK1 and Src homology 2
domain binding.";
J. Biol. Chem. 283:1480-1491(2008).
[36]
SUBCELLULAR LOCATION, AND INTERACTION WITH PTPN6.
PubMed=19591923; DOI=10.1016/j.cellsig.2009.06.010;
Sephton C.F., Zhang D., Lehmann T.M., Pennington P.R., Scheid M.P.,
Mousseau D.D.;
"The nuclear localization of 3'-phosphoinositide-dependent kinase-1 is
dependent on its association with the protein tyrosine phosphatase
SHP-1.";
Cell. Signal. 21:1634-1644(2009).
[37]
SUBCELLULAR LOCATION.
PubMed=19276999; DOI=10.1097/WNR.0b013e328329a41a;
Alajajian B.B., Fletcher L., Isgor E., Jimenez D.F., Digicaylioglu M.;
"IGF-I regulated phosphorylation and translocation of PDK-1 in
neurons.";
NeuroReport 20:579-583(2009).
[38]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[39]
PHOSPHORYLATION AT THR-354 BY MELK, PHOSPHORYLATION AT SER-394 AND
SER-398 BY MAP3K5, AND MUTAGENESIS OF THR-354; SER-394 AND SER-398.
PubMed=22544756; DOI=10.1074/jbc.M111.331827;
Seong H.A., Jung H., Manoharan R., Ha H.;
"PDK1 phosphorylation at Thr354 by murine protein serine/threonine
kinase 38 contributes to the negative regulation of PDK1 activity.";
J. Biol. Chem. 287:20811-20822(2012).
[40]
UBIQUITINATION, AND DEUBIQUITINATION BY USP4.
PubMed=22347420; DOI=10.1371/journal.pone.0031003;
Uras I.Z., List T., Nijman S.M.;
"Ubiquitin-specific protease 4 inhibits mono-ubiquitination of the
master growth factor signaling kinase PDK1.";
PLoS ONE 7:E31003-E31003(2012).
[41]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[42]
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 71-359 IN COMPLEX WITH ATP.
PubMed=12169624; DOI=10.1093/emboj/cdf437;
Biondi R.M., Komander D., Thomas C.C., Lizcano J.M., Deak M.,
Alessi D.R., van Aalten D.M.;
"High resolution crystal structure of the human PDK1 catalytic domain
defines the regulatory phosphopeptide docking site.";
EMBO J. 21:4219-4228(2002).
[43]
X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 51-360 IN COMPLEX WITH ATP.
PubMed=15741170; DOI=10.1074/jbc.M500977200;
Komander D., Kular G., Deak M., Alessi D.R., van Aalten D.M.;
"Role of T-loop phosphorylation in PDK1 activation, stability, and
substrate binding.";
J. Biol. Chem. 280:18797-18802(2005).
[44]
X-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS) OF 74-359, AND PHOSPHORYLATION
AT SER-241.
PubMed=15772071; DOI=10.1074/jbc.M501367200;
Feldman R.I., Wu J.M., Polokoff M.A., Kochanny M.J., Dinter H.,
Zhu D., Biroc S.L., Alicke B., Bryant J., Yuan S., Buckman B.O.,
Lentz D., Ferrer M., Whitlow M., Adler M., Finster S., Chang Z.,
Arnaiz D.O.;
"Novel small molecule inhibitors of 3-phosphoinositide-dependent
kinase-1.";
J. Biol. Chem. 280:19867-19874(2005).
[45]
X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 409-556, SUBUNIT, ENZYME
REGULATION, AND MUTAGENESIS OF THR-513.
PubMed=20978239; DOI=10.1126/scisignal.2000738;
Masters T.A., Calleja V., Armoogum D.A., Marsh R.J., Applebee C.J.,
Laguerre M., Bain A.J., Larijani B.;
"Regulation of 3-phosphoinositide-dependent protein kinase 1 activity
by homodimerization in live cells.";
Sci. Signal. 3:RA78-RA78(2010).
[46]
X-RAY CRYSTALLOGRAPHY (1.43 ANGSTROMS) OF 51-359 IN COMPLEX WITH ATP,
AND DOMAIN.
PubMed=22999883; DOI=10.1016/j.chembiol.2012.07.017;
Busschots K., Lopez-Garcia L.A., Lammi C., Stroba A., Zeuzem S.,
Piiper A., Alzari P.M., Neimanis S., Arencibia J.M., Engel M.,
Schulze J.O., Biondi R.M.;
"Substrate-selective inhibition of protein kinase PDK1 by small
compounds that bind to the PIF-pocket allosteric docking site.";
Chem. Biol. 19:1152-1163(2012).
-!- 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 Ca(2+) entry
and Ca(2+)-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. Isoform 3 is catalytically
inactive. {ECO:0000269|PubMed:10226025,
ECO:0000269|PubMed:10480933, ECO:0000269|PubMed:10995762,
ECO:0000269|PubMed:12167717, ECO:0000269|PubMed:14585963,
ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:16207722,
ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:17327236,
ECO:0000269|PubMed:17371830, ECO:0000269|PubMed:18835241,
ECO:0000269|PubMed:9094314, ECO:0000269|PubMed:9445476,
ECO:0000269|PubMed:9707564, ECO:0000269|PubMed:9768361}.
-!- 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-373 and Tyr-376 residues. The
14-3-3 protein YWHAQ acts as a negative regulator by association
with the residues surrounding the Ser-241 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-373 and Tyr-376 by INSR in response
to insulin. {ECO:0000269|PubMed:12177059,
ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:18616680,
ECO:0000269|PubMed:20978239}.
-!- SUBUNIT: 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-241
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. {ECO:0000269|PubMed:10226025,
ECO:0000269|PubMed:10995762, ECO:0000269|PubMed:12177059,
ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:14604990,
ECO:0000269|PubMed:15210700, ECO:0000269|PubMed:16207722,
ECO:0000269|PubMed:16251192, ECO:0000269|PubMed:16314505,
ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:18024423,
ECO:0000269|PubMed:18616680, ECO:0000269|PubMed:19591923,
ECO:0000269|PubMed:20978239}.
-!- INTERACTION:
P31749:AKT1; NbExp=4; IntAct=EBI-717097, EBI-296087;
Q00005:PPP2R2B; NbExp=8; IntAct=EBI-717097, EBI-1052159;
O75385:ULK1; NbExp=2; IntAct=EBI-717097, EBI-908831;
P27348:YWHAQ; NbExp=3; IntAct=EBI-717097, EBI-359854;
Q8IUH5:ZDHHC17; NbExp=3; IntAct=EBI-9087775, EBI-524753;
-!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane;
Peripheral membrane protein. Cell junction, focal adhesion.
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-241 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.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=5;
Name=1;
IsoId=O15530-1; Sequence=Displayed;
Name=2;
IsoId=O15530-2; Sequence=VSP_004894;
Name=3;
IsoId=O15530-3; Sequence=VSP_004895;
Name=4;
IsoId=O15530-4; Sequence=VSP_041902;
Name=5;
IsoId=O15530-5; Sequence=VSP_044796;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Appears to be expressed ubiquitously. The Tyr-
9 phosphorylated form is markedly increased in diseased tissue
compared with normal tissue from lung, liver, colon and breast.
{ECO:0000269|PubMed:18024423}.
-!- INDUCTION: Stimulated by insulin, and the oxidants hydrogen
peroxide and peroxovanadate.
-!- DOMAIN: The PH domain plays a pivotal role in the localization and
nuclear import of PDPK1 and is also essential for its
homodimerization.
-!- DOMAIN: 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.
{ECO:0000305|PubMed:22999883}.
-!- PTM: Phosphorylation on Ser-241 in the activation loop is required
for full activity. PDPK1 itself can autophosphorylate Ser-241,
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-
373 and Tyr-376 by INSR in response to insulin. Palmitate
negatively regulates autophosphorylation at Ser-241 and palmitate-
induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ
negatively regulates its ability to phosphorylate PKB/AKT1.
Phosphorylation at Thr-354 by MELK partially inhibits kinase
activity, the inhibition is cooperatively enhanced by
phosphorylation at Ser-394 and Ser-398 by MAP3K5. {ECO:0000250,
ECO:0000269|PubMed:10455013, ECO:0000269|PubMed:11481331,
ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15743829,
ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:16780920,
ECO:0000269|PubMed:22544756, ECO:0000269|Ref.8}.
-!- PTM: Autophosphorylated; autophosphorylation is inhibited by the
apoptotic C-terminus cleavage product of PKN2. {ECO:0000250}.
-!- PTM: Monoubiquitinated in the kinase domain, deubiquitinated by
USP4.
-!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
protein kinase family. PDPK1 subfamily. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=BAD93072.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
-----------------------------------------------------------------------
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-----------------------------------------------------------------------
EMBL; AF017995; AAC51825.1; -; mRNA.
EMBL; Y15056; CAA75341.1; -; mRNA.
EMBL; CR536517; CAG38755.1; -; mRNA.
EMBL; AB209835; BAD93072.1; ALT_INIT; mRNA.
EMBL; AC093525; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC141586; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC006339; AAH06339.2; -; mRNA.
EMBL; BC012103; AAH12103.1; -; mRNA.
EMBL; BC033494; AAH33494.1; -; mRNA.
CCDS; CCDS10472.1; -. [O15530-1]
CCDS; CCDS10473.1; -. [O15530-4]
CCDS; CCDS58411.1; -. [O15530-5]
RefSeq; NP_001248745.1; NM_001261816.1. [O15530-5]
RefSeq; NP_002604.1; NM_002613.4. [O15530-1]
RefSeq; NP_112558.2; NM_031268.5. [O15530-4]
UniGene; Hs.459691; -.
PDB; 1H1W; X-ray; 2.00 A; A=71-359.
PDB; 1OKY; X-ray; 2.30 A; A=51-360.
PDB; 1OKZ; X-ray; 2.51 A; A=51-360.
PDB; 1UU3; X-ray; 1.70 A; A=51-360.
PDB; 1UU7; X-ray; 1.90 A; A=51-360.
PDB; 1UU8; X-ray; 2.50 A; A=51-360.
PDB; 1UU9; X-ray; 1.95 A; A=72-357.
PDB; 1UVR; X-ray; 2.81 A; A=71-359.
PDB; 1W1D; X-ray; 1.50 A; A=409-556.
PDB; 1W1G; X-ray; 1.45 A; A=409-556.
PDB; 1W1H; X-ray; 1.45 A; A/B/C/D=409-556.
PDB; 1Z5M; X-ray; 2.17 A; A=74-359.
PDB; 2BIY; X-ray; 1.95 A; A=51-360.
PDB; 2PE0; X-ray; 2.35 A; A=74-359.
PDB; 2PE1; X-ray; 2.14 A; A=74-359.
PDB; 2PE2; X-ray; 2.13 A; A=74-359.
PDB; 2R7B; X-ray; 2.70 A; A=48-359.
PDB; 2VKI; X-ray; 1.80 A; A=409-556.
PDB; 2XCH; X-ray; 2.00 A; A=51-359.
PDB; 2XCK; X-ray; 2.30 A; A=51-359.
PDB; 3H9O; X-ray; 2.30 A; A=51-359.
PDB; 3HRC; X-ray; 1.91 A; A=50-359.
PDB; 3HRF; X-ray; 1.90 A; A=50-359.
PDB; 3ION; X-ray; 2.40 A; A=48-359.
PDB; 3IOP; X-ray; 2.20 A; A=48-359.
PDB; 3NAX; X-ray; 1.75 A; A=66-362.
PDB; 3NAY; X-ray; 2.60 A; A/B=66-362.
PDB; 3NUN; X-ray; 2.20 A; A=67-358.
PDB; 3NUS; X-ray; 2.75 A; A=73-358.
PDB; 3NUU; X-ray; 1.98 A; A=73-358.
PDB; 3NUY; X-ray; 2.10 A; A=73-358.
PDB; 3ORX; X-ray; 2.20 A; A/B/C/D/E/F/G/H=51-359.
PDB; 3ORZ; X-ray; 2.00 A; A/B/C/D=51-359.
PDB; 3OTU; X-ray; 2.10 A; A=51-359.
PDB; 3PWY; X-ray; 3.50 A; A=51-359.
PDB; 3QC4; X-ray; 1.80 A; A/B=51-359.
PDB; 3QCQ; X-ray; 2.50 A; A=48-359.
PDB; 3QCS; X-ray; 2.49 A; A=48-359.
PDB; 3QCX; X-ray; 2.30 A; A=48-359.
PDB; 3QCY; X-ray; 2.20 A; A=48-359.
PDB; 3QD0; X-ray; 1.99 A; A=48-359.
PDB; 3QD3; X-ray; 2.00 A; A=48-359.
PDB; 3QD4; X-ray; 2.30 A; A=48-359.
PDB; 3RCJ; X-ray; 1.70 A; A=50-359.
PDB; 3RWP; X-ray; 1.92 A; A=51-359.
PDB; 3RWQ; X-ray; 2.55 A; A=51-359.
PDB; 3SC1; X-ray; 2.70 A; A=50-359.
PDB; 4A06; X-ray; 2.00 A; A=50-359.
PDB; 4A07; X-ray; 1.85 A; A=50-359.
PDB; 4AW0; X-ray; 1.43 A; A=51-359.
PDB; 4AW1; X-ray; 1.68 A; A=51-359.
PDB; 4CT1; X-ray; 1.85 A; A=50-359.
PDB; 4CT2; X-ray; 1.25 A; A=50-359.
PDB; 4RQK; X-ray; 1.55 A; A=50-359.
PDB; 4RQV; X-ray; 1.50 A; A=50-359.
PDB; 4RRV; X-ray; 1.41 A; A=50-359.
PDB; 4XX9; X-ray; 1.40 A; A=50-359.
PDB; 5ACK; X-ray; 1.24 A; A=50-359.
PDB; 5HKM; X-ray; 2.10 A; A=51-359.
PDB; 5HNG; X-ray; 3.01 A; A=51-359.
PDB; 5HO7; X-ray; 3.00 A; A=51-359.
PDB; 5HO8; X-ray; 2.70 A; A=51-359.
PDB; 5LVL; X-ray; 1.40 A; A=50-359.
PDB; 5LVM; X-ray; 1.26 A; A=50-359.
PDB; 5LVN; X-ray; 1.38 A; A=50-359.
PDB; 5LVO; X-ray; 1.09 A; A=50-359.
PDB; 5LVP; X-ray; 2.50 A; A/B/C/D=50-359.
PDB; 5MRD; X-ray; 1.41 A; A=50-359.
PDBsum; 1H1W; -.
PDBsum; 1OKY; -.
PDBsum; 1OKZ; -.
PDBsum; 1UU3; -.
PDBsum; 1UU7; -.
PDBsum; 1UU8; -.
PDBsum; 1UU9; -.
PDBsum; 1UVR; -.
PDBsum; 1W1D; -.
PDBsum; 1W1G; -.
PDBsum; 1W1H; -.
PDBsum; 1Z5M; -.
PDBsum; 2BIY; -.
PDBsum; 2PE0; -.
PDBsum; 2PE1; -.
PDBsum; 2PE2; -.
PDBsum; 2R7B; -.
PDBsum; 2VKI; -.
PDBsum; 2XCH; -.
PDBsum; 2XCK; -.
PDBsum; 3H9O; -.
PDBsum; 3HRC; -.
PDBsum; 3HRF; -.
PDBsum; 3ION; -.
PDBsum; 3IOP; -.
PDBsum; 3NAX; -.
PDBsum; 3NAY; -.
PDBsum; 3NUN; -.
PDBsum; 3NUS; -.
PDBsum; 3NUU; -.
PDBsum; 3NUY; -.
PDBsum; 3ORX; -.
PDBsum; 3ORZ; -.
PDBsum; 3OTU; -.
PDBsum; 3PWY; -.
PDBsum; 3QC4; -.
PDBsum; 3QCQ; -.
PDBsum; 3QCS; -.
PDBsum; 3QCX; -.
PDBsum; 3QCY; -.
PDBsum; 3QD0; -.
PDBsum; 3QD3; -.
PDBsum; 3QD4; -.
PDBsum; 3RCJ; -.
PDBsum; 3RWP; -.
PDBsum; 3RWQ; -.
PDBsum; 3SC1; -.
PDBsum; 4A06; -.
PDBsum; 4A07; -.
PDBsum; 4AW0; -.
PDBsum; 4AW1; -.
PDBsum; 4CT1; -.
PDBsum; 4CT2; -.
PDBsum; 4RQK; -.
PDBsum; 4RQV; -.
PDBsum; 4RRV; -.
PDBsum; 4XX9; -.
PDBsum; 5ACK; -.
PDBsum; 5HKM; -.
PDBsum; 5HNG; -.
PDBsum; 5HO7; -.
PDBsum; 5HO8; -.
PDBsum; 5LVL; -.
PDBsum; 5LVM; -.
PDBsum; 5LVN; -.
PDBsum; 5LVO; -.
PDBsum; 5LVP; -.
PDBsum; 5MRD; -.
ProteinModelPortal; O15530; -.
SMR; O15530; -.
BioGrid; 111196; 61.
DIP; DIP-38372N; -.
ELM; O15530; -.
IntAct; O15530; 59.
MINT; O15530; -.
STRING; 9606.ENSP00000344220; -.
BindingDB; O15530; -.
ChEMBL; CHEMBL2534; -.
DrugBank; DB07132; 1-{2-OXO-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-5-YL}UREA.
DrugBank; DB07033; 5-HYDROXY-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-2-ONE.
DrugBank; DB01933; 7-Hydroxystaurosporine.
DrugBank; DB00482; Celecoxib.
DrugBank; DB04522; Phosphonoserine.
DrugBank; DB03777; Rbt205 Inhibitor.
DrugBank; DB02010; Staurosporine.
GuidetoPHARMACOLOGY; 1519; -.
MoonDB; O15530; Predicted.
iPTMnet; O15530; -.
PhosphoSitePlus; O15530; -.
BioMuta; PDPK1; -.
EPD; O15530; -.
MaxQB; O15530; -.
PaxDb; O15530; -.
PeptideAtlas; O15530; -.
PRIDE; O15530; -.
ProteomicsDB; 48736; -.
ProteomicsDB; 48737; -. [O15530-2]
ProteomicsDB; 48738; -. [O15530-3]
ProteomicsDB; 48739; -. [O15530-4]
DNASU; 5170; -.
Ensembl; ENST00000268673; ENSP00000268673; ENSG00000140992. [O15530-4]
Ensembl; ENST00000342085; ENSP00000344220; ENSG00000140992. [O15530-1]
Ensembl; ENST00000441549; ENSP00000395357; ENSG00000140992. [O15530-5]
GeneID; 5170; -.
KEGG; hsa:5170; -.
UCSC; uc002cqs.5; human. [O15530-1]
CTD; 5170; -.
DisGeNET; 5170; -.
EuPathDB; HostDB:ENSG00000140992.18; -.
GeneCards; PDPK1; -.
H-InvDB; HIX0038570; -.
H-InvDB; HIX0038793; -.
HGNC; HGNC:8816; PDPK1.
HPA; CAB004272; -.
HPA; HPA035199; -.
HPA; HPA068961; -.
MIM; 605213; gene.
neXtProt; NX_O15530; -.
OpenTargets; ENSG00000140992; -.
PharmGKB; PA33160; -.
eggNOG; KOG0592; Eukaryota.
eggNOG; ENOG410XRT8; LUCA.
GeneTree; ENSGT00920000149082; -.
HOGENOM; HOG000233026; -.
HOVERGEN; HBG098357; -.
InParanoid; O15530; -.
KO; K06276; -.
OMA; IPWSLEL; -.
OrthoDB; EOG091G06CX; -.
PhylomeDB; O15530; -.
TreeFam; TF105423; -.
BRENDA; 2.7.11.1; 2681.
Reactome; R-HSA-114604; GPVI-mediated activation cascade.
Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
Reactome; R-HSA-165158; Activation of AKT2.
Reactome; R-HSA-202424; Downstream TCR signaling.
Reactome; R-HSA-2730905; Role of LAT2/NTAL/LAB on calcium mobilization.
Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
Reactome; R-HSA-354192; Integrin alphaIIb beta3 signaling.
Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling.
Reactome; R-HSA-392451; G beta:gamma signalling through PI3Kgamma.
Reactome; R-HSA-444257; RSK activation.
Reactome; R-HSA-5218920; VEGFR2 mediated vascular permeability.
Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation.
Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling.
Reactome; R-HSA-5625740; RHO GTPases activate PKNs.
Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
SABIO-RK; O15530; -.
SignaLink; O15530; -.
SIGNOR; O15530; -.
ChiTaRS; PDPK1; human.
EvolutionaryTrace; O15530; -.
GeneWiki; Phosphoinositide-dependent_kinase-1; -.
GenomeRNAi; 5170; -.
PRO; PR:O15530; -.
Proteomes; UP000005640; Chromosome 16.
Bgee; ENSG00000140992; -.
CleanEx; HS_PDK1; -.
CleanEx; HS_PDPK1; -.
ExpressionAtlas; O15530; baseline and differential.
Genevisible; O15530; HS.
GO; GO:0042995; C:cell projection; IDA:BHF-UCL.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
GO; GO:0043204; C:perikaryon; IEA:Ensembl.
GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
GO; GO:0004676; F:3-phosphoinositide-dependent protein kinase activity; IDA:BHF-UCL.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0005158; F:insulin receptor binding; IEA:Ensembl.
GO; GO:0016301; F:kinase activity; TAS:Reactome.
GO; GO:0016004; F:phospholipase activator activity; IMP:BHF-UCL.
GO; GO:0043274; F:phospholipase binding; IPI:BHF-UCL.
GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc.
GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
GO; GO:0019722; P:calcium-mediated signaling; IMP:BHF-UCL.
GO; GO:0016477; P:cell migration; IMP:BHF-UCL.
GO; GO:1990416; P:cellular response to brain-derived neurotrophic factor stimulus; IEA:Ensembl.
GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IMP:BHF-UCL.
GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IMP:BHF-UCL.
GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IMP:UniProtKB.
GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
GO; GO:0048041; P:focal adhesion assembly; IEA:Ensembl.
GO; GO:0006972; P:hyperosmotic response; IEA:Ensembl.
GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:BHF-UCL.
GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:BHF-UCL.
GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IEA:Ensembl.
GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:BHF-UCL.
GO; GO:0030168; P:platelet activation; TAS:Reactome.
GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL.
GO; GO:0010518; P:positive regulation of phospholipase activity; IMP:BHF-UCL.
GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IMP:BHF-UCL.
GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:BHF-UCL.
GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IMP:BHF-UCL.
GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:BHF-UCL.
GO; GO:0046777; P:protein autophosphorylation; TAS:UniProtKB.
GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
GO; GO:0043304; P:regulation of mast cell degranulation; IEA:Ensembl.
GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:UniProtKB-KW.
GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; TAS:Reactome.
GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
GO; GO:0003323; P:type B pancreatic cell development; IEA:Ensembl.
CDD; cd01262; PH_PDK1; 1.
Gene3D; 2.30.29.30; -; 1.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR033931; PDK1-typ_PH.
InterPro; IPR039046; PDPK1.
InterPro; IPR011993; PH-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR008271; Ser/Thr_kinase_AS.
PANTHER; PTHR24356:SF163; PTHR24356:SF163; 1.
Pfam; PF14593; PH_3; 1.
Pfam; PF00069; Pkinase; 1.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Activator; Alternative splicing;
ATP-binding; Cell junction; Cell membrane; Complete proteome;
Cytoplasm; Direct protein sequencing; Kinase; Membrane;
Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
Serine/threonine-protein kinase; Transcription;
Transcription regulation; Transferase; Ubl conjugation.
CHAIN 1 556 3-phosphoinositide-dependent protein
kinase 1.
/FTId=PRO_0000086500.
DOMAIN 82 342 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
DOMAIN 459 550 PH.
NP_BIND 92 94 ATP. {ECO:0000269|PubMed:12169624,
ECO:0000269|PubMed:15741170,
ECO:0000269|PubMed:22999883}.
NP_BIND 160 162 ATP. {ECO:0000269|PubMed:12169624,
ECO:0000269|PubMed:15741170,
ECO:0000269|PubMed:22999883}.
REGION 113 157 PIF-pocket.
{ECO:0000305|PubMed:22999883}.
COMPBIAS 389 398 Poly-Ser.
ACT_SITE 205 205 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10027}.
BINDING 111 111 ATP. {ECO:0000269|PubMed:12169624,
ECO:0000269|PubMed:15741170,
ECO:0000269|PubMed:22999883}.
BINDING 166 166 ATP. {ECO:0000269|PubMed:12169624,
ECO:0000269|PubMed:15741170,
ECO:0000269|PubMed:22999883}.
BINDING 209 209 ATP; via carbonyl oxygen.
{ECO:0000269|PubMed:22999883}.
BINDING 223 223 ATP. {ECO:0000269|PubMed:12169624,
ECO:0000269|PubMed:15741170,
ECO:0000269|PubMed:22999883}.
MOD_RES 9 9 Phosphotyrosine; by SRC and INSR.
{ECO:0000269|PubMed:11481331,
ECO:0000269|PubMed:14585963,
ECO:0000269|PubMed:16314505}.
MOD_RES 25 25 Phosphoserine.
{ECO:0000269|PubMed:10455013}.
MOD_RES 241 241 Phosphoserine; by autocatalysis.
{ECO:0000269|PubMed:10455013,
ECO:0000269|PubMed:11481331,
ECO:0000269|PubMed:15772071,
ECO:0000269|PubMed:16780920,
ECO:0000269|Ref.8}.
MOD_RES 304 304 N6-acetyllysine.
{ECO:0000250|UniProtKB:Q9Z2A0}.
MOD_RES 354 354 Phosphothreonine; by MELK.
{ECO:0000269|PubMed:22544756}.
MOD_RES 373 373 Phosphotyrosine; by SRC and INSR.
{ECO:0000269|PubMed:11481331,
ECO:0000269|PubMed:14585963,
ECO:0000269|PubMed:16314505}.
MOD_RES 376 376 Phosphotyrosine; by SRC and INSR.
{ECO:0000269|PubMed:11481331,
ECO:0000269|PubMed:14585963,
ECO:0000269|PubMed:16314505}.
MOD_RES 393 393 Phosphoserine.
{ECO:0000269|PubMed:10455013}.
MOD_RES 394 394 Phosphoserine; by MAP3K5.
{ECO:0000269|PubMed:22544756}.
MOD_RES 396 396 Phosphoserine.
{ECO:0000269|PubMed:10455013,
ECO:0000269|PubMed:15743829}.
MOD_RES 398 398 Phosphoserine; by MAP3K5.
{ECO:0000269|PubMed:22544756}.
MOD_RES 410 410 Phosphoserine.
{ECO:0000269|PubMed:10455013}.
MOD_RES 501 501 Phosphoserine; by PKC/PRKCQ.
{ECO:0000250|UniProtKB:Q9Z2A0}.
MOD_RES 513 513 Phosphothreonine; by autocatalysis.
{ECO:0000269|PubMed:16780920}.
MOD_RES 529 529 Phosphoserine; by PKC/PRKCQ.
{ECO:0000250|UniProtKB:Q9Z2A0}.
VAR_SEQ 1 50 Missing (in isoform 2). {ECO:0000305}.
/FTId=VSP_004894.
VAR_SEQ 110 237 IKILEKRHIIKENKVPYVTRERDVMSRLDHPFFVKLYFTFQ
DDEKLYFGLSYAKNGELLKYIRKIGSFDETCTRFYTAEIVS
ALEYLHGKGIIHRDLKPENILLNEDMHIQITDFGTAKVLSP
ESKQA -> T (in isoform 4).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_041902.
VAR_SEQ 238 263 Missing (in isoform 3).
{ECO:0000303|PubMed:9445477}.
/FTId=VSP_004895.
VAR_SEQ 448 556 WHQFVENNLILKMGPVDKRKGLFARRRQLLLTEGPHLYYVD
PVNKVLKGEIPWSQELRPEAKNFKTFFVHTPNRTYYLMDPS
GNAHKWCRKIQEVWRQRYQSHPDAAVQ -> CLTGRII
(in isoform 5). {ECO:0000303|Ref.5}.
/FTId=VSP_044796.
MUTAGEN 9 9 Y->F: Slight reduction in pervanadate-
stimulated tyrosine phosphorylation.
{ECO:0000269|PubMed:11481331}.
MUTAGEN 25 25 S->A: No effect.
{ECO:0000269|PubMed:10455013}.
MUTAGEN 241 241 S->A: No activation.
{ECO:0000269|PubMed:10455013}.
MUTAGEN 277 277 A->V: 3-fold increase in kinase activity.
{ECO:0000269|PubMed:10364160}.
MUTAGEN 354 354 T->A: Abolishes phosphorylation by MELK.
{ECO:0000269|PubMed:22544756}.
MUTAGEN 373 373 Y->F: Reduction in basal activity.
{ECO:0000269|PubMed:11481331}.
MUTAGEN 376 376 Y->F: Reduction in basal activity.
{ECO:0000269|PubMed:11481331}.
MUTAGEN 393 393 S->A: No effect.
{ECO:0000269|PubMed:10455013}.
MUTAGEN 394 394 S->A: Abolishes phosphorylation by
MAP3K5; when associated with A-398.
{ECO:0000269|PubMed:22544756}.
MUTAGEN 396 396 S->A: No effect.
{ECO:0000269|PubMed:10455013}.
MUTAGEN 398 398 S->A: Abolishes phosphorylation by
MAP3K5; when associated with A-394.
{ECO:0000269|PubMed:22544756}.
MUTAGEN 410 410 S->A: No effect.
{ECO:0000269|PubMed:10455013}.
MUTAGEN 474 474 R->A: No PDGF-dependent translocation to
the membrane.
{ECO:0000269|PubMed:9637919}.
MUTAGEN 513 513 T->E: Enhanced kinase activity towards
PKB. {ECO:0000269|PubMed:20978239}.
HELIX 79 81 {ECO:0000244|PDB:5LVO}.
STRAND 82 90 {ECO:0000244|PDB:5LVO}.
STRAND 95 101 {ECO:0000244|PDB:5LVO}.
TURN 102 104 {ECO:0000244|PDB:5LVO}.
STRAND 107 114 {ECO:0000244|PDB:5LVO}.
HELIX 115 120 {ECO:0000244|PDB:5LVO}.
HELIX 124 136 {ECO:0000244|PDB:5LVO}.
STRAND 145 150 {ECO:0000244|PDB:5LVO}.
STRAND 152 159 {ECO:0000244|PDB:5LVO}.
STRAND 163 166 {ECO:0000244|PDB:3PWY}.
HELIX 167 174 {ECO:0000244|PDB:5LVO}.
HELIX 179 198 {ECO:0000244|PDB:5LVO}.
HELIX 208 210 {ECO:0000244|PDB:5LVO}.
STRAND 211 213 {ECO:0000244|PDB:5LVO}.
STRAND 219 221 {ECO:0000244|PDB:5LVO}.
HELIX 224 226 {ECO:0000244|PDB:3ORX}.
TURN 232 235 {ECO:0000244|PDB:5LVO}.
STRAND 238 240 {ECO:0000244|PDB:3OTU}.
HELIX 246 248 {ECO:0000244|PDB:5LVO}.
HELIX 251 256 {ECO:0000244|PDB:5LVO}.
HELIX 261 277 {ECO:0000244|PDB:5LVO}.
HELIX 287 295 {ECO:0000244|PDB:5LVO}.
STRAND 303 305 {ECO:0000244|PDB:3QD3}.
HELIX 307 316 {ECO:0000244|PDB:5LVO}.
HELIX 321 323 {ECO:0000244|PDB:5LVO}.
HELIX 328 330 {ECO:0000244|PDB:5LVO}.
HELIX 333 337 {ECO:0000244|PDB:5LVO}.
HELIX 340 342 {ECO:0000244|PDB:5LVO}.
HELIX 347 352 {ECO:0000244|PDB:5LVO}.
HELIX 412 415 {ECO:0000244|PDB:1W1G}.
STRAND 416 420 {ECO:0000244|PDB:1W1G}.
STRAND 423 426 {ECO:0000244|PDB:1W1G}.
HELIX 432 445 {ECO:0000244|PDB:1W1G}.
HELIX 449 451 {ECO:0000244|PDB:1W1G}.
TURN 452 454 {ECO:0000244|PDB:1W1G}.
STRAND 457 467 {ECO:0000244|PDB:1W1G}.
STRAND 470 479 {ECO:0000244|PDB:1W1G}.
TURN 480 482 {ECO:0000244|PDB:1W1G}.
STRAND 483 488 {ECO:0000244|PDB:1W1G}.
TURN 489 492 {ECO:0000244|PDB:1W1G}.
STRAND 493 498 {ECO:0000244|PDB:1W1G}.
STRAND 505 518 {ECO:0000244|PDB:1W1G}.
STRAND 521 526 {ECO:0000244|PDB:1W1G}.
HELIX 532 547 {ECO:0000244|PDB:1W1G}.
SEQUENCE 556 AA; 63152 MW; ED8C0306DC4D0653 CRC64;
MARTTSQLYD AVPIQSSVVL CSCPSPSMVR TQTESSTPPG IPGGSRQGPA MDGTAAEPRP
GAGSLQHAQP PPQPRKKRPE DFKFGKILGE GSFSTVVLAR ELATSREYAI KILEKRHIIK
ENKVPYVTRE RDVMSRLDHP FFVKLYFTFQ DDEKLYFGLS YAKNGELLKY IRKIGSFDET
CTRFYTAEIV SALEYLHGKG IIHRDLKPEN ILLNEDMHIQ ITDFGTAKVL SPESKQARAN
SFVGTAQYVS PELLTEKSAC KSSDLWALGC IIYQLVAGLP PFRAGNEYLI FQKIIKLEYD
FPEKFFPKAR DLVEKLLVLD ATKRLGCEEM EGYGPLKAHP FFESVTWENL HQQTPPKLTA
YLPAMSEDDE DCYGNYDNLL SQFGCMQVSS SSSSHSLSAS DTGLPQRSGS NIEQYIHDLD
SNSFELDLQF SEDEKRLLLE KQAGGNPWHQ FVENNLILKM GPVDKRKGLF ARRRQLLLTE
GPHLYYVDPV NKVLKGEIPW SQELRPEAKN FKTFFVHTPN RTYYLMDPSG NAHKWCRKIQ
EVWRQRYQSH PDAAVQ


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