PDPK1_HUMAN
ID PDPK1_HUMAN Reviewed; 556 AA.
AC O15530; H0Y4Z0; Q59EH6; Q6FI20; Q8IV52; Q9BRD5;
DT 18-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 234.
DE RecName: Full=3-phosphoinositide-dependent protein kinase 1;
DE Short=hPDK1;
DE EC=2.7.11.1;
GN Name=PDPK1; Synonyms=PDK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION IN PHOSPHORYLATION OF
RP PKB/AKT1.
RX PubMed=9094314; DOI=10.1016/s0960-9822(06)00122-9;
RA Alessi D.R., James S.R., Downes C.P., Holmes A.B., Gaffney P.R.J.,
RA Reese C.B., Cohen P.;
RT "Characterization of a 3-phosphoinositide-dependent protein kinase which
RT phosphorylates and activates protein kinase B alpha.";
RL Curr. Biol. 7:261-269(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9368760; DOI=10.1016/s0960-9822(06)00336-8;
RA Alessi D.R., Deak M., Casamayor A., Caudwell F.B., Morrice N.A.,
RA Norman D.G., Gaffney P.R.J., Reese C.B., MacDougall C.N., Harbison D.,
RA Ashworth A., Bownes M.;
RT "3-phosphoinositide-dependent protein kinase-1 (PDK1): structural and
RT functional homology with the Drosophila DSTPK61 kinase.";
RL Curr. Biol. 7:776-789(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Myeloid;
RX PubMed=9445477; DOI=10.1126/science.279.5351.710;
RA Stephens L.R., Anderson K.E., Stokoe D., Erdjument-Bromage H.,
RA Painter G.F., Holmes A.B., Gaffney P.R.J., Reese C.B., McCormick F.,
RA Tempst P., Coadwell W.J., Hawkins P.T.;
RT "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-
RT trisphosphate-dependent activation of protein kinase B.";
RL Science 279:710-714(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RT "Homo sapiens protein coding cDNA.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC TISSUE=Brain, Kidney, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PROTEIN SEQUENCE OF 60-75; 87-100; 184-199; 239-257 AND 284-293,
RP PHOSPHORYLATION AT SER-241, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [9]
RP MUTAGENESIS OF ARG-474, AND ALTERNATIVE SPLICING.
RX PubMed=9637919; DOI=10.1016/s0960-9822(98)70274-x;
RA Anderson K.E., Coadwell W.J., Stephens L.R., Hawkins P.T.;
RT "Translocation of PDK-1 to the plasma membrane is important in allowing
RT PDK-1 to activate protein kinase B.";
RL Curr. Biol. 8:684-691(1998).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF PRKCZ.
RX PubMed=9768361; DOI=10.1016/s0960-9822(98)70444-0;
RA Chou M.M., Hou W., Johnson J., Graham L.K., Lee M.H., Chen C.S.,
RA Newton A.C., Schaffhausen B.S., Toker A.;
RT "Regulation of protein kinase C zeta by PI 3-kinase and PDK-1.";
RL Curr. Biol. 8:1069-1077(1998).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF PRKACA.
RX PubMed=9707564; DOI=10.1073/pnas.95.17.9849;
RA Cheng X., Ma Y., Moore M., Hemmings B.A., Taylor S.S.;
RT "Phosphorylation and activation of cAMP-dependent protein kinase by
RT phosphoinositide-dependent protein kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:9849-9854(1998).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF RPS6KB1.
RX PubMed=9445476; DOI=10.1126/science.279.5351.707;
RA Pullen N., Dennis P.B., Andjelkovic M., Dufner A., Kozma S.C.,
RA Hemmings B.A., Thomas G.;
RT "Phosphorylation and activation of p70s6k by PDK1.";
RL Science 279:707-710(1998).
RN [13]
RP PHOSPHORYLATION AT SER-25; SER-241; SER-393; SER-396 AND SER-410, AND
RP MUTAGENESIS OF SER-25; SER-241; SER-393; SER-396 AND SER-410.
RX PubMed=10455013; DOI=10.1042/bj3420287;
RA Casamayor A., Morrice N.A., Alessi D.R.;
RT "Phosphorylation of Ser-241 is essential for the activity of 3-
RT phosphoinositide-dependent protein kinase-1: identification of five sites
RT of phosphorylation in vivo.";
RL Biochem. J. 342:287-292(1999).
RN [14]
RP MUTAGENESIS OF ALA-277.
RX PubMed=10364160; DOI=10.1101/gad.13.11.1438;
RA Paradis S., Ailion M., Toker A., Thomas J.H., Ruvkun G.;
RT "A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase
RT signals that regulate diapause in Caenorhabditis elegans.";
RL Genes Dev. 13:1438-1452(1999).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF RPS6KA3.
RX PubMed=10480933; DOI=10.1074/jbc.274.38.27168;
RA Jensen C.J., Buch M.-B., Krag T.O., Hemmings B.A., Gammeltoft S.,
RA Froedin M.;
RT "90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-
RT phosphoinositide-dependent protein kinase-1.";
RL J. Biol. Chem. 274:27168-27176(1999).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF PAK1, AND INTERACTION WITH PAK1.
RX PubMed=10995762; DOI=10.1074/jbc.m006553200;
RA King C.C., Gardiner E.M., Zenke F.T., Bohl B.P., Newton A.C.,
RA Hemmings B.A., Bokoch G.M.;
RT "p21-activated kinase (PAK1) is phosphorylated and activated by 3-
RT phosphoinositide-dependent kinase-1 (PDK1).";
RL J. Biol. Chem. 275:41201-41209(2000).
RN [17]
RP PHOSPHORYLATION AT TYR-9; SER-241; TYR-373 AND TYR-376, AND MUTAGENESIS OF
RP TYR-9; TYR-373 AND TYR-376.
RX PubMed=11481331; DOI=10.1074/jbc.m105916200;
RA Park J., Hill M.M., Hess D., Brazil D.P., Hofsteenge J., Hemmings B.A.;
RT "Identification of tyrosine phosphorylation sites on 3-phosphoinositide-
RT dependent protein kinase-1 (PDK1) and their role in regulating kinase
RT activity.";
RL J. Biol. Chem. 276:37459-37471(2001).
RN [18]
RP ACTIVITY REGULATION, AND INTERACTION WITH YWHAH AND YWHAQ.
RX PubMed=12177059; DOI=10.1074/jbc.m205141200;
RA Sato S., Fujita N., Tsuruo T.;
RT "Regulation of kinase activity of 3-phosphoinositide-dependent protein
RT kinase-1 by binding to 14-3-3.";
RL J. Biol. Chem. 277:39360-39367(2002).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF PKB/AKT1.
RX PubMed=12167717; DOI=10.1128/mcb.22.17.6247-6260.2002;
RA Scheid M.P., Marignani P.A., Woodgett J.R.;
RT "Multiple phosphoinositide 3-kinase-dependent steps in activation of
RT protein kinase B.";
RL Mol. Cell. Biol. 22:6247-6260(2002).
RN [20]
RP FUNCTION, PHOSPHORYLATION AT TYR-9; TYR-373 AND TYR-376 BY SRC, INTERACTION
RP WITH PTK2B, AND SUBCELLULAR LOCATION.
RX PubMed=14585963; DOI=10.1128/mcb.23.22.8019-8029.2003;
RA Taniyama Y., Weber D.S., Rocic P., Hilenski L., Akers M.L., Park J.,
RA Hemmings B.A., Alexander R.W., Griendling K.K.;
RT "Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal
RT adhesions.";
RL Mol. Cell. Biol. 23:8019-8029(2003).
RN [21]
RP FUNCTION IN PHOSPHORYLATION OF SGK3, AND INTERACTION WITH SGK3.
RX PubMed=14604990; DOI=10.1074/jbc.m309653200;
RA Nilsen T., Slagsvold T., Skjerpen C.S., Brech A., Stenmark H., Olsnes S.;
RT "Peroxisomal targeting as a tool for assaying protein-protein interactions
RT in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1
RT in vivo in a phosphorylation-dependent manner.";
RL J. Biol. Chem. 279:4794-4801(2004).
RN [22]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH GRB14.
RX PubMed=15210700; DOI=10.1074/jbc.m405340200;
RA King C.C., Newton A.C.;
RT "The adaptor protein Grb14 regulates the localization of 3-
RT phosphoinositide-dependent kinase-1.";
RL J. Biol. Chem. 279:37518-37527(2004).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF AKT1, AND INTERACTION WITH PKN2.
RX PubMed=10226025; DOI=10.1016/s0960-9822(99)80186-9;
RA Balendran A., Casamayor A., Deak M., Paterson A., Gaffney P., Currie R.,
RA Downes C.P., Alessi D.R.;
RT "PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived
RT from the carboxyl terminus of PRK2.";
RL Curr. Biol. 9:393-404(1999).
RN [24]
RP REVIEW ON FUNCTION.
RX PubMed=15209375; DOI=10.1016/j.semcdb.2003.12.022;
RA Mora A., Komander D., van Aalten D.M., Alessi D.R.;
RT "PDK1, the master regulator of AGC kinase signal transduction.";
RL Semin. Cell Dev. Biol. 15:161-170(2004).
RN [25]
RP FUNCTION IN PHOSPHORYLATION OF IKKB, AND INTERACTION WITH IKKB.
RX PubMed=16207722; DOI=10.1074/jbc.m506235200;
RA Tanaka H., Fujita N., Tsuruo T.;
RT "3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta
RT (IkkB) phosphorylation activates NF-kappaB signaling.";
RL J. Biol. Chem. 280:40965-40973(2005).
RN [26]
RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH STRAP.
RX PubMed=16251192; DOI=10.1074/jbc.m507539200;
RA Seong H.A., Jung H., Choi H.S., Kim K.T., Ha H.;
RT "Regulation of transforming growth factor-beta signaling and PDK1 kinase
RT activity by physical interaction between PDK1 and serine-threonine kinase
RT receptor-associated protein.";
RL J. Biol. Chem. 280:42897-42908(2005).
RN [27]
RP PHOSPHORYLATION AT SER-396, AND SUBCELLULAR LOCATION.
RX PubMed=15743829; DOI=10.1128/mcb.25.6.2347-2363.2005;
RA Scheid M.P., Parsons M., Woodgett J.R.;
RT "Phosphoinositide-dependent phosphorylation of PDK1 regulates nuclear
RT translocation.";
RL Mol. Cell. Biol. 25:2347-2363(2005).
RN [28]
RP PHOSPHORYLATION AT TYR-9; TYR-373 AND TYR-376 BY INSR, AND INTERACTION WITH
RP INSR.
RX PubMed=16314505; DOI=10.1128/mcb.25.24.10803-10814.2005;
RA Fiory F., Alberobello A.T., Miele C., Oriente F., Esposito I., Corbo V.,
RA Ruvo M., Tizzano B., Rasmussen T.E., Gammeltoft S., Formisano P.,
RA Beguinot F.;
RT "Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by the
RT insulin receptor is necessary for insulin metabolic signaling.";
RL Mol. Cell. Biol. 25:10803-10814(2005).
RN [29]
RP PHOSPHORYLATION AT SER-241 AND THR-513.
RX PubMed=16780920; DOI=10.1016/j.bioorg.2006.05.002;
RA Gao X., Harris T.K.;
RT "Role of the PH domain in regulating in vitro autophosphorylation events
RT required for reconstitution of PDK1 catalytic activity.";
RL Bioorg. Chem. 34:200-223(2006).
RN [30]
RP FUNCTION, AND INTERACTION WITH SMAD2; SMAD3; SMAD4 AND SMAD7.
RX PubMed=17327236; DOI=10.1074/jbc.m609279200;
RA Seong H.A., Jung H., Kim K.T., Ha H.;
RT "3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth
RT factor-beta-induced signaling in a kinase-dependent manner through physical
RT interaction with Smad proteins.";
RL J. Biol. Chem. 282:12272-12289(2007).
RN [31]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17371830; DOI=10.1083/jcb.200607053;
RA Primo L., di Blasio L., Roca C., Droetto S., Piva R., Schaffhausen B.,
RA Bussolino F.;
RT "Essential role of PDK1 in regulating endothelial cell migration.";
RL J. Cell Biol. 176:1035-1047(2007).
RN [32]
RP FUNCTION IN PHOSPHORYLATION OF PKN2.
RX PubMed=18835241; DOI=10.1016/j.abb.2008.09.008;
RA Lim W.G., Chen X., Liu J.P., Tan B.J., Zhou S., Smith A., Lees N., Hou L.,
RA Gu F., Yu X.Y., Du Y., Smith D., Verma C., Liu K., Duan W.;
RT "The C-terminus of PRK2/PKNgamma is required for optimal activation by RhoA
RT in a GTP-dependent manner.";
RL Arch. Biochem. Biophys. 479:170-178(2008).
RN [33]
RP INTERACTION WITH NPRL2, AND ACTIVITY REGULATION.
RX PubMed=18616680; DOI=10.1111/j.1349-7006.2008.00874.x;
RA Kurata A., Katayama R., Watanabe T., Tsuruo T., Fujita N.;
RT "TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine
RT phosphorylation and its downstream signaling.";
RL Cancer Sci. 99:1827-1834(2008).
RN [34]
RP REVIEW ON FUNCTION.
RX PubMed=18802401; DOI=10.4161/cc.7.19.6810;
RA Bayascas J.R.;
RT "Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1
RT (PDK1) signalling pathways.";
RL Cell Cycle 7:2978-2982(2008).
RN [35]
RP INTERACTION WITH SRC; RASA1 AND CRK, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=18024423; DOI=10.1074/jbc.m706361200;
RA Yang K.J., Shin S., Piao L., Shin E., Li Y., Park K.A., Byun H.S., Won M.,
RA Hong J., Kweon G.R., Hur G.M., Seok J.H., Chun T., Brazil D.P.,
RA Hemmings B.A., Park J.;
RT "Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src
RT involves tyrosine phosphorylation of PDK1 and Src homology 2 domain
RT binding.";
RL J. Biol. Chem. 283:1480-1491(2008).
RN [36]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PTPN6.
RX PubMed=19591923; DOI=10.1016/j.cellsig.2009.06.010;
RA Sephton C.F., Zhang D., Lehmann T.M., Pennington P.R., Scheid M.P.,
RA Mousseau D.D.;
RT "The nuclear localization of 3'-phosphoinositide-dependent kinase-1 is
RT dependent on its association with the protein tyrosine phosphatase SHP-1.";
RL Cell. Signal. 21:1634-1644(2009).
RN [37]
RP SUBCELLULAR LOCATION.
RX PubMed=19276999; DOI=10.1097/wnr.0b013e328329a41a;
RA Alajajian B.B., Fletcher L., Isgor E., Jimenez D.F., Digicaylioglu M.;
RT "IGF-I regulated phosphorylation and translocation of PDK-1 in neurons.";
RL NeuroReport 20:579-583(2009).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [39]
RP PHOSPHORYLATION AT THR-354 BY MELK, PHOSPHORYLATION AT SER-394 AND SER-398
RP BY MAP3K5, AND MUTAGENESIS OF THR-354; SER-394 AND SER-398.
RX PubMed=22544756; DOI=10.1074/jbc.m111.331827;
RA Seong H.A., Jung H., Manoharan R., Ha H.;
RT "PDK1 phosphorylation at Thr354 by murine protein serine/threonine kinase
RT 38 contributes to the negative regulation of PDK1 activity.";
RL J. Biol. Chem. 287:20811-20822(2012).
RN [40]
RP UBIQUITINATION, AND DEUBIQUITINATION BY USP4.
RX PubMed=22347420; DOI=10.1371/journal.pone.0031003;
RA Uras I.Z., List T., Nijman S.M.;
RT "Ubiquitin-specific protease 4 inhibits mono-ubiquitination of the master
RT growth factor signaling kinase PDK1.";
RL PLoS ONE 7:E31003-E31003(2012).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 71-359 IN COMPLEX WITH ATP.
RX PubMed=12169624; DOI=10.1093/emboj/cdf437;
RA Biondi R.M., Komander D., Thomas C.C., Lizcano J.M., Deak M., Alessi D.R.,
RA van Aalten D.M.;
RT "High resolution crystal structure of the human PDK1 catalytic domain
RT defines the regulatory phosphopeptide docking site.";
RL EMBO J. 21:4219-4228(2002).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 51-360 IN COMPLEX WITH ATP.
RX PubMed=15741170; DOI=10.1074/jbc.m500977200;
RA Komander D., Kular G., Deak M., Alessi D.R., van Aalten D.M.;
RT "Role of T-loop phosphorylation in PDK1 activation, stability, and
RT substrate binding.";
RL J. Biol. Chem. 280:18797-18802(2005).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS) OF 74-359, AND PHOSPHORYLATION AT
RP SER-241.
RX PubMed=15772071; DOI=10.1074/jbc.m501367200;
RA Feldman R.I., Wu J.M., Polokoff M.A., Kochanny M.J., Dinter H., Zhu D.,
RA Biroc S.L., Alicke B., Bryant J., Yuan S., Buckman B.O., Lentz D.,
RA Ferrer M., Whitlow M., Adler M., Finster S., Chang Z., Arnaiz D.O.;
RT "Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-
RT 1.";
RL J. Biol. Chem. 280:19867-19874(2005).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 409-556, SUBUNIT, ACTIVITY
RP REGULATION, AND MUTAGENESIS OF THR-513.
RX PubMed=20978239; DOI=10.1126/scisignal.2000738;
RA Masters T.A., Calleja V., Armoogum D.A., Marsh R.J., Applebee C.J.,
RA Laguerre M., Bain A.J., Larijani B.;
RT "Regulation of 3-phosphoinositide-dependent protein kinase 1 activity by
RT homodimerization in live cells.";
RL Sci. Signal. 3:RA78-RA78(2010).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.43 ANGSTROMS) OF 51-359 IN COMPLEX WITH ATP, AND
RP DOMAIN.
RX PubMed=22999883; DOI=10.1016/j.chembiol.2012.07.017;
RA Busschots K., Lopez-Garcia L.A., Lammi C., Stroba A., Zeuzem S., Piiper A.,
RA Alzari P.M., Neimanis S., Arencibia J.M., Engel M., Schulze J.O.,
RA Biondi R.M.;
RT "Substrate-selective inhibition of protein kinase PDK1 by small compounds
RT that bind to the PIF-pocket allosteric docking site.";
RL Chem. Biol. 19:1152-1163(2012).
CC -!- FUNCTION: Serine/threonine kinase which acts as a master kinase,
CC phosphorylating and activating a subgroup of the AGC family of protein
CC kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2,
CC PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal
CC protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent
CC protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and
CC glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated
CC kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central
CC role in the transduction of signals from insulin by providing the
CC activating phosphorylation to PKB/AKT1, thus propagating the signal to
CC downstream targets controlling cell proliferation and survival, as well
CC as glucose and amino acid uptake and storage. Negatively regulates the
CC TGF-beta-induced signaling by: modulating the association of SMAD3 and
CC SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and
CC SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the
CC translocation of SMAD7 from the nucleus to the cytoplasm in response to
CC TGF-beta. Activates PPARG transcriptional activity and promotes
CC adipocyte differentiation. Activates the NF-kappa-B pathway via
CC phosphorylation of IKKB. The tyrosine phosphorylated form is crucial
CC for the regulation of focal adhesions by angiotensin II. Controls
CC proliferation, survival, and growth of developing pancreatic cells.
CC Participates in the regulation of Ca(2+) entry and Ca(2+)-activated
CC K(+) channels of mast cells. Essential for the motility of vascular
CC endothelial cells (ECs) and is involved in the regulation of their
CC chemotaxis. Plays a critical role in cardiac homeostasis by serving as
CC a dual effector for cell survival and beta-adrenergic response. Plays
CC an important role during thymocyte development by regulating the
CC expression of key nutrient receptors on the surface of pre-T cells and
CC mediating Notch-induced cell growth and proliferative responses.
CC Provides negative feedback inhibition to toll-like receptor-mediated
CC NF-kappa-B activation in macrophages. Isoform 3 is catalytically
CC inactive. {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10480933,
CC ECO:0000269|PubMed:10995762, ECO:0000269|PubMed:12167717,
CC ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:14604990,
CC ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16251192,
CC ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:17371830,
CC ECO:0000269|PubMed:18835241, ECO:0000269|PubMed:9094314,
CC ECO:0000269|PubMed:9445476, ECO:0000269|PubMed:9707564,
CC ECO:0000269|PubMed:9768361}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- ACTIVITY REGULATION: Homodimerization regulates its activity by
CC maintaining the kinase in an autoinhibitory conformation. NPRL2 down-
CC regulates its activity by interfering with tyrosine phosphorylation at
CC the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts
CC as a negative regulator by association with the residues surrounding
CC the Ser-241 residue. STRAP positively regulates its activity by
CC enhancing its autophosphorylation and by stimulating its dissociation
CC from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its
CC activity by stimulating its dissociation from YWHAQ. Activated by
CC phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to
CC insulin. {ECO:0000269|PubMed:12177059, ECO:0000269|PubMed:16251192,
CC ECO:0000269|PubMed:18616680, ECO:0000269|PubMed:20978239}.
CC -!- SUBUNIT: Homodimer in its autoinhibited state. Active as monomer.
CC Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus),
CC STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1
CC and CRK (via their SH2 domains). Interacts with SGK3 in a
CC phosphorylation-dependent manner. The tyrosine-phosphorylated form
CC interacts with PTPN6. The Ser-241 phosphorylated form interacts with
CC YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH
CC domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the
CC interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-
CC dependent kinase activity toward 'Ser-473' of AKT1 but also activates
CC its kinase activity toward PRKCD and PRKCZ.
CC {ECO:0000269|PubMed:10226025, ECO:0000269|PubMed:10995762,
CC ECO:0000269|PubMed:12177059, ECO:0000269|PubMed:14585963,
CC ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:15210700,
CC ECO:0000269|PubMed:16207722, ECO:0000269|PubMed:16251192,
CC ECO:0000269|PubMed:16314505, ECO:0000269|PubMed:17327236,
CC ECO:0000269|PubMed:18024423, ECO:0000269|PubMed:18616680,
CC ECO:0000269|PubMed:19591923, ECO:0000269|PubMed:20978239}.
CC -!- INTERACTION:
CC O15530; P31749: AKT1; NbExp=4; IntAct=EBI-717097, EBI-296087;
CC O15530; Q00005: PPP2R2B; NbExp=8; IntAct=EBI-717097, EBI-1052159;
CC O15530; O75385: ULK1; NbExp=2; IntAct=EBI-717097, EBI-908831;
CC O15530-4; P54252: ATXN3; NbExp=3; IntAct=EBI-9087775, EBI-946046;
CC O15530-4; P42858: HTT; NbExp=6; IntAct=EBI-9087775, EBI-466029;
CC O15530-4; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-9087775, EBI-1055254;
CC O15530-4; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-9087775, EBI-524753;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane; Peripheral
CC membrane protein. Cell junction, focal adhesion. Note=Tyrosine
CC phosphorylation seems to occur only at the cell membrane. Translocates
CC to the cell membrane following insulin stimulation by a mechanism that
CC involves binding to GRB14 and INSR. SRC and HSP90 promote its
CC localization to the cell membrane. Its nuclear localization is
CC dependent on its association with PTPN6 and its phosphorylation at Ser-
CC 396. Restricted to the nucleus in neuronal cells while in non-neuronal
CC cells it is found in the cytoplasm. The Ser-241 phosphorylated form is
CC distributed along the perinuclear region in neuronal cells while in
CC non-neuronal cells it is found in both the nucleus and the cytoplasm.
CC IGF1 transiently increases phosphorylation at Ser-241 of neuronal
CC PDPK1, resulting in its translocation to other cellular compartments.
CC The tyrosine-phosphorylated form colocalizes with PTK2B in focal
CC adhesions after angiotensin II stimulation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=O15530-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15530-2; Sequence=VSP_004894;
CC Name=3;
CC IsoId=O15530-3; Sequence=VSP_004895;
CC Name=4;
CC IsoId=O15530-4; Sequence=VSP_041902;
CC Name=5;
CC IsoId=O15530-5; Sequence=VSP_044796;
CC -!- TISSUE SPECIFICITY: Appears to be expressed ubiquitously. The Tyr-9
CC phosphorylated form is markedly increased in diseased tissue compared
CC with normal tissue from lung, liver, colon and breast.
CC {ECO:0000269|PubMed:18024423}.
CC -!- INDUCTION: Stimulated by insulin, and the oxidants hydrogen peroxide
CC and peroxovanadate.
CC -!- DOMAIN: The PH domain plays a pivotal role in the localization and
CC nuclear import of PDPK1 and is also essential for its homodimerization.
CC -!- DOMAIN: The PIF-pocket is a small lobe in the catalytic domain required
CC by the enzyme for the binding to the hydrophobic motif of its
CC substrates. It is an allosteric regulatory site that can accommodate
CC small compounds acting as allosteric inhibitors.
CC {ECO:0000305|PubMed:22999883}.
CC -!- PTM: Phosphorylation on Ser-241 in the activation loop is required for
CC full activity. PDPK1 itself can autophosphorylate Ser-241, leading to
CC its own activation. Autophosphorylation is inhibited by the apoptotic
CC C-terminus cleavage product of PKN2 (By similarity). Tyr-9
CC phosphorylation is critical for stabilization of both PDPK1 and the
CC PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation.
CC Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in
CC vascular smooth muscle in a calcium- and SRC-dependent manner.
CC Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to
CC insulin. Palmitate negatively regulates autophosphorylation at Ser-241
CC and palmitate-induced phosphorylation at Ser-529 and Ser-501 by
CC PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1.
CC Phosphorylation at Thr-354 by MELK partially inhibits kinase activity,
CC the inhibition is cooperatively enhanced by phosphorylation at Ser-394
CC and Ser-398 by MAP3K5. {ECO:0000250, ECO:0000269|PubMed:10455013,
CC ECO:0000269|PubMed:11481331, ECO:0000269|PubMed:14585963,
CC ECO:0000269|PubMed:15743829, ECO:0000269|PubMed:16314505,
CC ECO:0000269|PubMed:16780920, ECO:0000269|PubMed:22544756,
CC ECO:0000269|Ref.8}.
CC -!- PTM: Autophosphorylated; autophosphorylation is inhibited by the
CC apoptotic C-terminus cleavage product of PKN2. {ECO:0000250}.
CC -!- PTM: Monoubiquitinated in the kinase domain, deubiquitinated by USP4.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. PDPK1 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD93072.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF017995; AAC51825.1; -; mRNA.
DR EMBL; Y15056; CAA75341.1; -; mRNA.
DR EMBL; CR536517; CAG38755.1; -; mRNA.
DR EMBL; AB209835; BAD93072.1; ALT_INIT; mRNA.
DR EMBL; AC093525; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC141586; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006339; AAH06339.2; -; mRNA.
DR EMBL; BC012103; AAH12103.1; -; mRNA.
DR EMBL; BC033494; AAH33494.1; -; mRNA.
DR CCDS; CCDS10472.1; -. [O15530-1]
DR CCDS; CCDS10473.1; -. [O15530-4]
DR CCDS; CCDS58411.1; -. [O15530-5]
DR RefSeq; NP_001248745.1; NM_001261816.1. [O15530-5]
DR RefSeq; NP_002604.1; NM_002613.4. [O15530-1]
DR RefSeq; NP_112558.2; NM_031268.5. [O15530-4]
DR PDB; 1H1W; X-ray; 2.00 A; A=71-359.
DR PDB; 1OKY; X-ray; 2.30 A; A=51-360.
DR PDB; 1OKZ; X-ray; 2.51 A; A=51-360.
DR PDB; 1UU3; X-ray; 1.70 A; A=51-360.
DR PDB; 1UU7; X-ray; 1.90 A; A=51-360.
DR PDB; 1UU8; X-ray; 2.50 A; A=51-360.
DR PDB; 1UU9; X-ray; 1.95 A; A=72-357.
DR PDB; 1UVR; X-ray; 2.81 A; A=71-359.
DR PDB; 1W1D; X-ray; 1.50 A; A=409-556.
DR PDB; 1W1G; X-ray; 1.45 A; A=409-556.
DR PDB; 1W1H; X-ray; 1.45 A; A/B/C/D=409-556.
DR PDB; 1Z5M; X-ray; 2.17 A; A=74-359.
DR PDB; 2BIY; X-ray; 1.95 A; A=51-360.
DR PDB; 2PE0; X-ray; 2.35 A; A=74-359.
DR PDB; 2PE1; X-ray; 2.14 A; A=74-359.
DR PDB; 2PE2; X-ray; 2.13 A; A=74-359.
DR PDB; 2R7B; X-ray; 2.70 A; A=48-359.
DR PDB; 2VKI; X-ray; 1.80 A; A=409-556.
DR PDB; 2XCH; X-ray; 2.00 A; A=51-359.
DR PDB; 2XCK; X-ray; 2.30 A; A=51-359.
DR PDB; 3H9O; X-ray; 2.30 A; A=51-359.
DR PDB; 3HRC; X-ray; 1.91 A; A=50-359.
DR PDB; 3HRF; X-ray; 1.90 A; A=50-359.
DR PDB; 3ION; X-ray; 2.40 A; A=48-359.
DR PDB; 3IOP; X-ray; 2.20 A; A=48-359.
DR PDB; 3NAX; X-ray; 1.75 A; A=66-362.
DR PDB; 3NAY; X-ray; 2.60 A; A/B=66-362.
DR PDB; 3NUN; X-ray; 2.20 A; A=67-358.
DR PDB; 3NUS; X-ray; 2.75 A; A=73-358.
DR PDB; 3NUU; X-ray; 1.98 A; A=73-358.
DR PDB; 3NUY; X-ray; 2.10 A; A=73-358.
DR PDB; 3ORX; X-ray; 2.20 A; A/B/C/D/E/F/G/H=51-359.
DR PDB; 3ORZ; X-ray; 2.00 A; A/B/C/D=51-359.
DR PDB; 3OTU; X-ray; 2.10 A; A=51-359.
DR PDB; 3PWY; X-ray; 3.50 A; A=51-359.
DR PDB; 3QC4; X-ray; 1.80 A; A/B=51-359.
DR PDB; 3QCQ; X-ray; 2.50 A; A=48-359.
DR PDB; 3QCS; X-ray; 2.49 A; A=48-359.
DR PDB; 3QCX; X-ray; 2.30 A; A=48-359.
DR PDB; 3QCY; X-ray; 2.20 A; A=48-359.
DR PDB; 3QD0; X-ray; 1.99 A; A=48-359.
DR PDB; 3QD3; X-ray; 2.00 A; A=48-359.
DR PDB; 3QD4; X-ray; 2.30 A; A=48-359.
DR PDB; 3RCJ; X-ray; 1.70 A; A=50-359.
DR PDB; 3RWP; X-ray; 1.92 A; A=51-359.
DR PDB; 3RWQ; X-ray; 2.55 A; A=51-359.
DR PDB; 3SC1; X-ray; 2.70 A; A=50-359.
DR PDB; 4A06; X-ray; 2.00 A; A=50-359.
DR PDB; 4A07; X-ray; 1.85 A; A=50-359.
DR PDB; 4AW0; X-ray; 1.43 A; A=51-359.
DR PDB; 4AW1; X-ray; 1.68 A; A=51-359.
DR PDB; 4CT1; X-ray; 1.85 A; A=50-359.
DR PDB; 4CT2; X-ray; 1.25 A; A=50-359.
DR PDB; 4RQK; X-ray; 1.55 A; A=50-359.
DR PDB; 4RQV; X-ray; 1.50 A; A=50-359.
DR PDB; 4RRV; X-ray; 1.41 A; A=50-359.
DR PDB; 4XX9; X-ray; 1.40 A; A=50-359.
DR PDB; 5ACK; X-ray; 1.24 A; A=50-359.
DR PDB; 5HKM; X-ray; 2.10 A; A=51-359.
DR PDB; 5HNG; X-ray; 3.01 A; A=51-359.
DR PDB; 5HO7; X-ray; 3.00 A; A=51-359.
DR PDB; 5HO8; X-ray; 2.70 A; A=51-359.
DR PDB; 5LVL; X-ray; 1.40 A; A=50-359.
DR PDB; 5LVM; X-ray; 1.26 A; A=50-359.
DR PDB; 5LVN; X-ray; 1.38 A; A=50-359.
DR PDB; 5LVO; X-ray; 1.09 A; A=50-359.
DR PDB; 5LVP; X-ray; 2.50 A; A/B/C/D=50-359.
DR PDB; 5MRD; X-ray; 1.41 A; A=50-359.
DR PDB; 6WJQ; X-ray; 2.71 A; C/D=2-16.
DR PDBsum; 1H1W; -.
DR PDBsum; 1OKY; -.
DR PDBsum; 1OKZ; -.
DR PDBsum; 1UU3; -.
DR PDBsum; 1UU7; -.
DR PDBsum; 1UU8; -.
DR PDBsum; 1UU9; -.
DR PDBsum; 1UVR; -.
DR PDBsum; 1W1D; -.
DR PDBsum; 1W1G; -.
DR PDBsum; 1W1H; -.
DR PDBsum; 1Z5M; -.
DR PDBsum; 2BIY; -.
DR PDBsum; 2PE0; -.
DR PDBsum; 2PE1; -.
DR PDBsum; 2PE2; -.
DR PDBsum; 2R7B; -.
DR PDBsum; 2VKI; -.
DR PDBsum; 2XCH; -.
DR PDBsum; 2XCK; -.
DR PDBsum; 3H9O; -.
DR PDBsum; 3HRC; -.
DR PDBsum; 3HRF; -.
DR PDBsum; 3ION; -.
DR PDBsum; 3IOP; -.
DR PDBsum; 3NAX; -.
DR PDBsum; 3NAY; -.
DR PDBsum; 3NUN; -.
DR PDBsum; 3NUS; -.
DR PDBsum; 3NUU; -.
DR PDBsum; 3NUY; -.
DR PDBsum; 3ORX; -.
DR PDBsum; 3ORZ; -.
DR PDBsum; 3OTU; -.
DR PDBsum; 3PWY; -.
DR PDBsum; 3QC4; -.
DR PDBsum; 3QCQ; -.
DR PDBsum; 3QCS; -.
DR PDBsum; 3QCX; -.
DR PDBsum; 3QCY; -.
DR PDBsum; 3QD0; -.
DR PDBsum; 3QD3; -.
DR PDBsum; 3QD4; -.
DR PDBsum; 3RCJ; -.
DR PDBsum; 3RWP; -.
DR PDBsum; 3RWQ; -.
DR PDBsum; 3SC1; -.
DR PDBsum; 4A06; -.
DR PDBsum; 4A07; -.
DR PDBsum; 4AW0; -.
DR PDBsum; 4AW1; -.
DR PDBsum; 4CT1; -.
DR PDBsum; 4CT2; -.
DR PDBsum; 4RQK; -.
DR PDBsum; 4RQV; -.
DR PDBsum; 4RRV; -.
DR PDBsum; 4XX9; -.
DR PDBsum; 5ACK; -.
DR PDBsum; 5HKM; -.
DR PDBsum; 5HNG; -.
DR PDBsum; 5HO7; -.
DR PDBsum; 5HO8; -.
DR PDBsum; 5LVL; -.
DR PDBsum; 5LVM; -.
DR PDBsum; 5LVN; -.
DR PDBsum; 5LVO; -.
DR PDBsum; 5LVP; -.
DR PDBsum; 5MRD; -.
DR PDBsum; 6WJQ; -.
DR AlphaFoldDB; O15530; -.
DR SMR; O15530; -.
DR BioGRID; 111196; 145.
DR DIP; DIP-38372N; -.
DR ELM; O15530; -.
DR IntAct; O15530; 143.
DR MINT; O15530; -.
DR STRING; 9606.ENSP00000344220; -.
DR BindingDB; O15530; -.
DR ChEMBL; CHEMBL2534; -.
DR DrugBank; DB07132; 1-{2-OXO-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-5-YL}UREA.
DR DrugBank; DB06932; 10,11-dimethoxy-4-methyldibenzo[c,f]-2,7-naphthyridine-3,6-diamine.
DR DrugBank; DB07300; 2-(1H-imidazol-1-yl)-9-methoxy-8-(2-methoxyethoxy)benzo[c][2,7]naphthyridin-4-amine.
DR DrugBank; DB07456; 3-(1H-indol-3-yl)-4-(1-{2-[(2S)-1-methylpyrrolidinyl]ethyl}-1H-indol-3-yl)-1H-pyrrole-2,5-dione.
DR DrugBank; DB07457; 3-[1-(3-AMINOPROPYL)-1H-INDOL-3-YL]-4-(1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE.
DR DrugBank; DB07033; 5-HYDROXY-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-2-ONE.
DR DrugBank; DB01933; 7-Hydroxystaurosporine.
DR DrugBank; DB03777; Bisindolylmaleimide I.
DR DrugBank; DB01946; Bisindolylmaleimide VIII.
DR DrugBank; DB00482; Celecoxib.
DR DrugBank; DB04522; Dexfosfoserine.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB01863; Inositol 1,3,4,5-Tetrakisphosphate.
DR DrugBank; DB02010; Staurosporine.
DR DrugCentral; O15530; -.
DR GuidetoPHARMACOLOGY; 1519; -.
DR MoonDB; O15530; Predicted.
DR iPTMnet; O15530; -.
DR PhosphoSitePlus; O15530; -.
DR BioMuta; PDPK1; -.
DR CPTAC; CPTAC-1052; -.
DR CPTAC; CPTAC-1540; -.
DR EPD; O15530; -.
DR jPOST; O15530; -.
DR MassIVE; O15530; -.
DR MaxQB; O15530; -.
DR PaxDb; O15530; -.
DR PeptideAtlas; O15530; -.
DR PRIDE; O15530; -.
DR ProteomicsDB; 34858; -.
DR ProteomicsDB; 48736; -. [O15530-1]
DR ProteomicsDB; 48737; -. [O15530-2]
DR ProteomicsDB; 48738; -. [O15530-3]
DR ProteomicsDB; 48739; -. [O15530-4]
DR Antibodypedia; 3794; 993 antibodies from 47 providers.
DR DNASU; 5170; -.
DR Ensembl; ENST00000268673.11; ENSP00000268673.7; ENSG00000140992.19. [O15530-4]
DR Ensembl; ENST00000342085.9; ENSP00000344220.4; ENSG00000140992.19. [O15530-1]
DR Ensembl; ENST00000441549.7; ENSP00000395357.3; ENSG00000140992.19. [O15530-5]
DR GeneID; 5170; -.
DR KEGG; hsa:5170; -.
DR MANE-Select; ENST00000342085.9; ENSP00000344220.4; NM_002613.5; NP_002604.1.
DR UCSC; uc002cqs.5; human. [O15530-1]
DR CTD; 5170; -.
DR DisGeNET; 5170; -.
DR GeneCards; PDPK1; -.
DR HGNC; HGNC:8816; PDPK1.
DR HPA; ENSG00000140992; Low tissue specificity.
DR MIM; 605213; gene.
DR neXtProt; NX_O15530; -.
DR OpenTargets; ENSG00000140992; -.
DR PharmGKB; PA33160; -.
DR VEuPathDB; HostDB:ENSG00000140992; -.
DR eggNOG; KOG0592; Eukaryota.
DR GeneTree; ENSGT00940000155267; -.
DR InParanoid; O15530; -.
DR OMA; GYPSIRA; -.
DR OrthoDB; 1157543at2759; -.
DR PhylomeDB; O15530; -.
DR TreeFam; TF105423; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; O15530; -.
DR Reactome; R-HSA-114604; GPVI-mediated activation cascade.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-165158; Activation of AKT2.
DR Reactome; R-HSA-202424; Downstream TCR signaling.
DR Reactome; R-HSA-2730905; Role of LAT2/NTAL/LAB on calcium mobilization.
DR Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-HSA-354192; Integrin signaling.
DR Reactome; R-HSA-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-HSA-392451; G beta:gamma signalling through PI3Kgamma.
DR Reactome; R-HSA-444257; RSK activation.
DR Reactome; R-HSA-5218920; VEGFR2 mediated vascular permeability.
DR Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation.
DR Reactome; R-HSA-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-HSA-5625740; RHO GTPases activate PKNs.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
DR Reactome; R-HSA-9634635; Estrogen-stimulated signaling through PRKCZ.
DR Reactome; R-HSA-9755779; SARS-CoV-2 targets host intracellular signalling and regulatory pathways.
DR SABIO-RK; O15530; -.
DR SignaLink; O15530; -.
DR SIGNOR; O15530; -.
DR BioGRID-ORCS; 5170; 549 hits in 1121 CRISPR screens.
DR ChiTaRS; PDPK1; human.
DR EvolutionaryTrace; O15530; -.
DR GeneWiki; Phosphoinositide-dependent_kinase-1; -.
DR GenomeRNAi; 5170; -.
DR Pharos; O15530; Tchem.
DR PRO; PR:O15530; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; O15530; protein.
DR Bgee; ENSG00000140992; Expressed in secondary oocyte and 194 other tissues.
DR ExpressionAtlas; O15530; baseline and differential.
DR Genevisible; O15530; HS.
DR GO; GO:0042995; C:cell projection; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
DR GO; GO:0004676; F:3-phosphoinositide-dependent protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016004; F:phospholipase activator activity; IMP:BHF-UCL.
DR GO; GO:0043274; F:phospholipase binding; IPI:BHF-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc.
DR GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
DR GO; GO:0019722; P:calcium-mediated signaling; IMP:BHF-UCL.
DR GO; GO:0016477; P:cell migration; IMP:BHF-UCL.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IMP:BHF-UCL.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0006972; P:hyperosmotic response; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL.
DR GO; GO:0010518; P:positive regulation of phospholipase activity; IMP:BHF-UCL.
DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:BHF-UCL.
DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; IMP:BHF-UCL.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; TAS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0043304; P:regulation of mast cell degranulation; IEA:Ensembl.
DR GO; GO:0003323; P:type B pancreatic cell development; IEA:Ensembl.
DR CDD; cd01262; PH_PDK1; 1.
DR CDD; cd05581; STKc_PDK1; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR033931; PDK1-typ_PH.
DR InterPro; IPR039046; PDPK1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF14593; PH_3; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing; ATP-binding;
KW Cell junction; Cell membrane; Cytoplasm; Direct protein sequencing; Kinase;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Ubl conjugation.
FT CHAIN 1..556
FT /note="3-phosphoinositide-dependent protein kinase 1"
FT /id="PRO_0000086500"
FT DOMAIN 82..342
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 459..550
FT /note="PH"
FT REGION 26..80
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 113..157
FT /note="PIF-pocket"
FT /evidence="ECO:0000305|PubMed:22999883"
FT COMPBIAS 26..42
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 205
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 92..94
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12169624,
FT ECO:0000269|PubMed:15741170, ECO:0000269|PubMed:22999883"
FT BINDING 111
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12169624,
FT ECO:0000269|PubMed:15741170, ECO:0000269|PubMed:22999883"
FT BINDING 160..162
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12169624,
FT ECO:0000269|PubMed:15741170, ECO:0000269|PubMed:22999883"
FT BINDING 166
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12169624,
FT ECO:0000269|PubMed:15741170, ECO:0000269|PubMed:22999883"
FT BINDING 209
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:22999883"
FT BINDING 223
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:12169624,
FT ECO:0000269|PubMed:15741170, ECO:0000269|PubMed:22999883"
FT MOD_RES 9
FT /note="Phosphotyrosine; by SRC and INSR"
FT /evidence="ECO:0000269|PubMed:11481331,
FT ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16314505"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455013"
FT MOD_RES 241
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:10455013,
FT ECO:0000269|PubMed:11481331, ECO:0000269|PubMed:15772071,
FT ECO:0000269|PubMed:16780920, ECO:0000269|Ref.8"
FT MOD_RES 304
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2A0"
FT MOD_RES 354
FT /note="Phosphothreonine; by MELK"
FT /evidence="ECO:0000269|PubMed:22544756"
FT MOD_RES 373
FT /note="Phosphotyrosine; by SRC and INSR"
FT /evidence="ECO:0000269|PubMed:11481331,
FT ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16314505"
FT MOD_RES 376
FT /note="Phosphotyrosine; by SRC and INSR"
FT /evidence="ECO:0000269|PubMed:11481331,
FT ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:16314505"
FT MOD_RES 393
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455013"
FT MOD_RES 394
FT /note="Phosphoserine; by MAP3K5"
FT /evidence="ECO:0000269|PubMed:22544756"
FT MOD_RES 396
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455013,
FT ECO:0000269|PubMed:15743829"
FT MOD_RES 398
FT /note="Phosphoserine; by MAP3K5"
FT /evidence="ECO:0000269|PubMed:22544756"
FT MOD_RES 410
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455013"
FT MOD_RES 501
FT /note="Phosphoserine; by PKC/PRKCQ"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2A0"
FT MOD_RES 513
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16780920"
FT MOD_RES 529
FT /note="Phosphoserine; by PKC/PRKCQ"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2A0"
FT VAR_SEQ 1..50
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_004894"
FT VAR_SEQ 110..237
FT /note="IKILEKRHIIKENKVPYVTRERDVMSRLDHPFFVKLYFTFQDDEKLYFGLSY
FT AKNGELLKYIRKIGSFDETCTRFYTAEIVSALEYLHGKGIIHRDLKPENILLNEDMHIQ
FT ITDFGTAKVLSPESKQA -> T (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_041902"
FT VAR_SEQ 238..263
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9445477"
FT /id="VSP_004895"
FT VAR_SEQ 448..556
FT /note="WHQFVENNLILKMGPVDKRKGLFARRRQLLLTEGPHLYYVDPVNKVLKGEIP
FT WSQELRPEAKNFKTFFVHTPNRTYYLMDPSGNAHKWCRKIQEVWRQRYQSHPDAAVQ
FT -> CLTGRII (in isoform 5)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_044796"
FT MUTAGEN 9
FT /note="Y->F: Slight reduction in pervanadate-stimulated
FT tyrosine phosphorylation."
FT /evidence="ECO:0000269|PubMed:11481331"
FT MUTAGEN 25
FT /note="S->A: No effect."
FT /evidence="ECO:0000269|PubMed:10455013"
FT MUTAGEN 241
FT /note="S->A: No activation."
FT /evidence="ECO:0000269|PubMed:10455013"
FT MUTAGEN 277
FT /note="A->V: 3-fold increase in kinase activity."
FT /evidence="ECO:0000269|PubMed:10364160"
FT MUTAGEN 354
FT /note="T->A: Abolishes phosphorylation by MELK."
FT /evidence="ECO:0000269|PubMed:22544756"
FT MUTAGEN 373
FT /note="Y->F: Reduction in basal activity."
FT /evidence="ECO:0000269|PubMed:11481331"
FT MUTAGEN 376
FT /note="Y->F: Reduction in basal activity."
FT /evidence="ECO:0000269|PubMed:11481331"
FT MUTAGEN 393
FT /note="S->A: No effect."
FT /evidence="ECO:0000269|PubMed:10455013"
FT MUTAGEN 394
FT /note="S->A: Abolishes phosphorylation by MAP3K5; when
FT associated with A-398."
FT /evidence="ECO:0000269|PubMed:22544756"
FT MUTAGEN 396
FT /note="S->A: No effect."
FT /evidence="ECO:0000269|PubMed:10455013"
FT MUTAGEN 398
FT /note="S->A: Abolishes phosphorylation by MAP3K5; when
FT associated with A-394."
FT /evidence="ECO:0000269|PubMed:22544756"
FT MUTAGEN 410
FT /note="S->A: No effect."
FT /evidence="ECO:0000269|PubMed:10455013"
FT MUTAGEN 474
FT /note="R->A: No PDGF-dependent translocation to the
FT membrane."
FT /evidence="ECO:0000269|PubMed:9637919"
FT MUTAGEN 513
FT /note="T->E: Enhanced kinase activity towards PKB."
FT /evidence="ECO:0000269|PubMed:20978239"
FT TURN 7..9
FT /evidence="ECO:0007829|PDB:6WJQ"
FT HELIX 79..81
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 82..90
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 95..101
FT /evidence="ECO:0007829|PDB:5LVO"
FT TURN 102..104
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 107..114
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 115..120
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 124..136
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 145..150
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 152..159
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 163..166
FT /evidence="ECO:0007829|PDB:3PWY"
FT HELIX 167..174
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 179..198
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 208..210
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 211..213
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 224..226
FT /evidence="ECO:0007829|PDB:3ORX"
FT TURN 232..235
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 238..240
FT /evidence="ECO:0007829|PDB:3OTU"
FT HELIX 246..248
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 251..256
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 261..277
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 287..295
FT /evidence="ECO:0007829|PDB:5LVO"
FT STRAND 303..305
FT /evidence="ECO:0007829|PDB:3QD3"
FT HELIX 307..316
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 321..323
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 328..330
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 333..337
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 340..342
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 347..352
FT /evidence="ECO:0007829|PDB:5LVO"
FT HELIX 412..415
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 416..420
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 423..426
FT /evidence="ECO:0007829|PDB:1W1G"
FT HELIX 432..445
FT /evidence="ECO:0007829|PDB:1W1G"
FT HELIX 449..451
FT /evidence="ECO:0007829|PDB:1W1G"
FT TURN 452..454
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 457..467
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 470..479
FT /evidence="ECO:0007829|PDB:1W1G"
FT TURN 480..482
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 483..488
FT /evidence="ECO:0007829|PDB:1W1G"
FT TURN 489..492
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 493..498
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 505..518
FT /evidence="ECO:0007829|PDB:1W1G"
FT STRAND 521..526
FT /evidence="ECO:0007829|PDB:1W1G"
FT HELIX 532..547
FT /evidence="ECO:0007829|PDB:1W1G"
SQ 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
