SGK3_HUMAN
ID SGK3_HUMAN Reviewed; 496 AA.
AC Q96BR1; A8K5W3; B3KQC2; Q9P1Q7; Q9UKG5;
DT 22-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 192.
DE RecName: Full=Serine/threonine-protein kinase Sgk3;
DE EC=2.7.11.1;
DE AltName: Full=Cytokine-independent survival kinase;
DE AltName: Full=Serum/glucocorticoid-regulated kinase 3;
DE AltName: Full=Serum/glucocorticoid-regulated kinase-like;
GN Name=SGK3; Synonyms=CISK, SGKL;
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), PHOSPHORYLATION AT THR-320, AND
RP MUTAGENESIS OF SER-486.
RX PubMed=10548550; DOI=10.1042/bj3440189;
RA Kobayashi T., Deak M., Morrice N., Cohen P.;
RT "Characterization of the structure and regulation of two novel isoforms of
RT serum- and glucocorticoid-induced protein kinase.";
RL Biochem. J. 344:189-197(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10585774; DOI=10.1006/geno.1999.5969;
RA Dai F., Yu L., He H., Zhao Y., Yang J., Zhang X., Zhao S.;
RT "Cloning and mapping of a novel human Serum/Glucocorticoid regulated
RT kinase-like gene, SGKL, to chromosome 8q12.3-q13.1.";
RL Genomics 62:95-97(1999).
RN [3]
RP SEQUENCE REVISION.
RA Zhao Y.;
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Mammary gland;
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 [7]
RP FUNCTION IN PHOSPHORYLATION OF GSK3B, AND INTERACTION WITH GSK3B.
RX PubMed=12054501; DOI=10.1016/s0006-291x(02)00349-2;
RA Dai F., Yu L., He H., Chen Y., Yu J., Yang Y., Xu Y., Ling W., Zhao S.;
RT "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL)
RT phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9
RT through direct interaction.";
RL Biochem. Biophys. Res. Commun. 293:1191-1196(2002).
RN [8]
RP FUNCTION IN REGULATION OF NA(+)/K(+) ATPASE.
RX PubMed=12590200; DOI=10.1159/000068699;
RA Henke G., Setiawan I., Boehmer C., Lang F.;
RT "Activation of Na+/K+-ATPase by the serum and glucocorticoid-dependent
RT kinase isoforms.";
RL Kidney Blood Press. Res. 25:370-374(2002).
RN [9]
RP FUNCTION.
RX PubMed=12397388; DOI=10.1007/s00424-002-0873-2;
RA Gamper N., Fillon S., Feng Y., Friedrich B., Lang P.A., Henke G.,
RA Huber S.M., Kobayashi T., Cohen P., Lang F.;
RT "K(+) channel activation by all three isoforms of serum- and
RT glucocorticoid-dependent protein kinase SGK.";
RL Pflugers Arch. 445:60-66(2002).
RN [10]
RP FUNCTION IN REGULATION OF SCN5A.
RX PubMed=12650886; DOI=10.1016/s0008-6363(02)00837-4;
RA Boehmer C., Wilhelm V., Palmada M., Wallisch S., Henke G., Brinkmeier H.,
RA Cohen P., Pieske B., Lang F.;
RT "Serum and glucocorticoid inducible kinases in the regulation of the
RT cardiac sodium channel SCN5A.";
RL Cardiovasc. Res. 57:1079-1084(2003).
RN [11]
RP FUNCTION IN REGULATION OF SLC1A3/EAAT1.
RX PubMed=12911626; DOI=10.1046/j.1471-4159.2003.01937.x;
RA Boehmer C., Henke G., Schniepp R., Palmada M., Rothstein J.D., Broeer S.,
RA Lang F.;
RT "Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase
RT Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3
RT and protein kinase B.";
RL J. Neurochem. 86:1181-1188(2003).
RN [12]
RP FUNCTION IN REGULATION OF KCNE1 AND KCNQ1.
RX PubMed=12634932; DOI=10.1007/s00424-002-0982-y;
RA Embark H.M., Boehmer C., Vallon V., Luft F., Lang F.;
RT "Regulation of KCNE1-dependent K(+) current by the serum and
RT glucocorticoid-inducible kinase (SGK) isoforms.";
RL Pflugers Arch. 445:601-606(2003).
RN [13]
RP FUNCTION IN REGULATION OF SCNN1A/ENAC.
RX PubMed=12632189; DOI=10.1007/s00424-002-0993-8;
RA Friedrich B., Feng Y., Cohen P., Risler T., Vandewalle A., Broeer S.,
RA Wang J., Pearce D., Lang F.;
RT "The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the
RT epithelial Na+ channel alpha,beta,gamma-ENaC.";
RL Pflugers Arch. 445:693-696(2003).
RN [14]
RP FUNCTION IN REGULATION OF SLC34A2/NAPI-2B, AND FUNCTION IN PHOSPHORYLATION
RP OF NEDD4L.
RX PubMed=15044175; DOI=10.1152/ajpgi.00121.2003;
RA Palmada M., Dieter M., Speil A., Boehmer C., Mack A.F., Wagner H.J.,
RA Klingel K., Kandolf R., Murer H., Biber J., Closs E.I., Lang F.;
RT "Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin
RT ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1.";
RL Am. J. Physiol. 287:G143-G150(2004).
RN [15]
RP FUNCTION IN REGULATION OF SLC13A2/NADC1.
RX PubMed=14706641; DOI=10.1016/j.bbrc.2003.12.011;
RA Boehmer C., Embark H.M., Bauer A., Palmada M., Yun C.H., Weinman E.J.,
RA Endou H., Cohen P., Lahme S., Bichler K.H., Lang F.;
RT "Stimulation of renal Na+ dicarboxylate cotransporter 1 by Na+/H+ exchanger
RT regulating factor 2, serum and glucocorticoid inducible kinase isoforms,
RT and protein kinase B.";
RL Biochem. Biophys. Res. Commun. 313:998-1003(2004).
RN [16]
RP FUNCTION IN REGULATION OF TRPV5.
RX PubMed=15319523; DOI=10.1159/000080329;
RA Embark H.M., Setiawan I., Poppendieck S., van de Graaf S.F., Boehmer C.,
RA Palmada M., Wieder T., Gerstberger R., Cohen P., Yun C.C., Bindels R.J.,
RA Lang F.;
RT "Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating
RT factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms
RT SGK1 and SGK3 expressed in Xenopus oocytes.";
RL Cell. Physiol. Biochem. 14:203-212(2004).
RN [17]
RP INTERACTION WITH PDPK1, AND PHOSPHORYLATION BY PDPK1.
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 [18]
RP FUNCTION IN REGULATION OF KCNA3/KV1.3.
RX PubMed=15040001; DOI=10.1002/jcp.10430;
RA Henke G., Maier G., Wallisch S., Boehmer C., Lang F.;
RT "Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase
RT Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1.";
RL J. Cell. Physiol. 199:194-199(2004).
RN [19]
RP FUNCTION IN REGULATION OF BSND.
RX PubMed=15496163; DOI=10.1111/j.1523-1755.2004.00966.x;
RA Embark H.M., Boehmer C., Palmada M., Rajamanickam J., Wyatt A.W.,
RA Wallisch S., Capasso G., Waldegger P., Seyberth H.W., Waldegger S.,
RA Lang F.;
RT "Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the
RT serum- and glucocorticoid-dependent kinases.";
RL Kidney Int. 66:1918-1925(2004).
RN [20]
RP FUNCTION IN REGULATION OF SLC1A5/ASCT2.
RX PubMed=15845389; DOI=10.1016/j.bbrc.2005.03.159;
RA Palmada M., Speil A., Jeyaraj S., Boehmer C., Lang F.;
RT "The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid
RT transporter ASCT2.";
RL Biochem. Biophys. Res. Commun. 331:272-277(2005).
RN [21]
RP FUNCTION IN REGULATION OF SLC1A7/EAAT5.
RX PubMed=15737648; DOI=10.1016/j.bbrc.2005.02.035;
RA Boehmer C., Rajamanickam J., Schniepp R., Kohler K., Wulff P., Kuhl D.,
RA Palmada M., Lang F.;
RT "Regulation of the excitatory amino acid transporter EAAT5 by the serum and
RT glucocorticoid dependent kinases SGK1 and SGK3.";
RL Biochem. Biophys. Res. Commun. 329:738-742(2005).
RN [22]
RP FUNCTION IN REGULATION OF SLC6A8.
RX PubMed=16036218; DOI=10.1016/j.bbrc.2005.06.164;
RA Shojaiefard M., Christie D.L., Lang F.;
RT "Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1
RT and SGK3.";
RL Biochem. Biophys. Res. Commun. 334:742-746(2005).
RN [23]
RP FUNCTION IN REGULATION OF KCNH2/HERG.
RX PubMed=17167223; DOI=10.1159/000097666;
RA Maier G., Palmada M., Rajamanickam J., Shumilina E., Boehmer C., Lang F.;
RT "Upregulation of HERG channels by the serum and glucocorticoid inducible
RT kinase isoform SGK3.";
RL Cell. Physiol. Biochem. 18:177-186(2006).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ITHC/AIP4, AND
RP PHOSPHORYLATION AT SER-486.
RX PubMed=16888620; DOI=10.1038/sj.emboj.7601267;
RA Slagsvold T., Marchese A., Brech A., Stenmark H.;
RT "CISK attenuates degradation of the chemokine receptor CXCR4 via the
RT ubiquitin ligase AIP4.";
RL EMBO J. 25:3738-3749(2006).
RN [25]
RP PHOSPHORYLATION AT THR-320 AND SER-486, AND MUTAGENESIS OF ARG-90 AND
RP LYS-191.
RX PubMed=16790420; DOI=10.1074/jbc.m604333200;
RA Tessier M., Woodgett J.R.;
RT "Role of the Phox homology domain and phosphorylation in activation of
RT serum and glucocorticoid-regulated kinase-3.";
RL J. Biol. Chem. 281:23978-23989(2006).
RN [26]
RP FUNCTION IN REGULATION OF TRPV6.
RX PubMed=18005662; DOI=10.1016/j.febslet.2007.11.006;
RA Boehmer C., Palmada M., Kenngott C., Lindner R., Klaus F., Laufer J.,
RA Lang F.;
RT "Regulation of the epithelial calcium channel TRPV6 by the serum and
RT glucocorticoid-inducible kinase isoforms SGK1 and SGK3.";
RL FEBS Lett. 581:5586-5590(2007).
RN [27]
RP FUNCTION IN PHOSPHORYLATION OF FLII, AND INTERACTION WITH FLII.
RX PubMed=19293151; DOI=10.1074/jbc.m807770200;
RA Xu J., Liao L., Qin J., Xu J., Liu D., Songyang Z.;
RT "Identification of Flightless-I as a substrate of the cytokine-independent
RT survival kinase CISK.";
RL J. Biol. Chem. 284:14377-14385(2009).
RN [28]
RP FUNCTION IN REGULATION OF SLC6A19.
RX PubMed=20511718; DOI=10.1159/000315092;
RA Boehmer C., Sopjani M., Klaus F., Lindner R., Laufer J., Jeyaraj S.,
RA Lang F., Palmada M.;
RT "The serum and glucocorticoid inducible kinases SGK1-3 stimulate the
RT neutral amino acid transporter SLC6A19.";
RL Cell. Physiol. Biochem. 25:723-732(2010).
RN [29]
RP FUNCTION IN REGULATION OF SLC9A3/NHE3, AND SUBCELLULAR LOCATION.
RX PubMed=21865597; DOI=10.1091/mbc.e11-04-0328;
RA He P., Lee S.J., Lin S., Seidler U., Lang F., Fejes-Toth G.,
RA Naray-Fejes-Toth A., Yun C.C.;
RT "Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates
RT acute activation of Na+/H+ exchanger NHE3 by glucocorticoids.";
RL Mol. Biol. Cell 22:3812-3825(2011).
RN [30]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=21084382; DOI=10.1210/me.2010-0294;
RA Wang Y., Zhou D., Phung S., Masri S., Smith D., Chen S.;
RT "SGK3 is an estrogen-inducible kinase promoting estrogen-mediated survival
RT of breast cancer cells.";
RL Mol. Endocrinol. 25:72-82(2011).
RN [31]
RP REVIEW.
RX PubMed=16460280; DOI=10.1146/annurev.physiol.68.040104.131654;
RA Loffing J., Flores S.Y., Staub O.;
RT "Sgk kinases and their role in epithelial transport.";
RL Annu. Rev. Physiol. 68:461-490(2006).
RN [32]
RP REVIEW ON FUNCTION.
RX PubMed=20919962; DOI=10.3109/08977194.2010.518616;
RA Bruhn M.A., Pearson R.B., Hannan R.D., Sheppard K.E.;
RT "Second AKT: the rise of SGK in cancer signalling.";
RL Growth Factors 28:394-408(2010).
RN [33]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-92.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [34]
RP VARIANT [LARGE SCALE ANALYSIS] PRO-355.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine-protein kinase which is involved in the
CC regulation of a wide variety of ion channels, membrane transporters,
CC cell growth, proliferation, survival and migration. Up-regulates Na(+)
CC channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1,
CC KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6,
CC chloride channel: BSND, creatine transporter: SLC6A8,
CC Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent
CC phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters:
CC SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1,
CC SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and
CC GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+)
CC ATPase. Plays a role in the regulation of renal tubular phosphate
CC transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively
CC regulates ER transcription activity through phosphorylation of FLII.
CC Negatively regulates the function of ITCH/AIP4 via its phosphorylation
CC and thereby prevents CXCR4 from being efficiently sorted to lysosomes.
CC {ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12397388,
CC ECO:0000269|PubMed:12590200, ECO:0000269|PubMed:12632189,
CC ECO:0000269|PubMed:12634932, ECO:0000269|PubMed:12650886,
CC ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:14706641,
CC ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15044175,
CC ECO:0000269|PubMed:15319523, ECO:0000269|PubMed:15496163,
CC ECO:0000269|PubMed:15737648, ECO:0000269|PubMed:15845389,
CC ECO:0000269|PubMed:16036218, ECO:0000269|PubMed:16888620,
CC ECO:0000269|PubMed:17167223, ECO:0000269|PubMed:18005662,
CC ECO:0000269|PubMed:19293151, ECO:0000269|PubMed:20511718,
CC ECO:0000269|PubMed:21865597}.
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: Two specific sites, one in the kinase domain (Thr-
CC 320) and the other in the C-terminal regulatory region (Ser-486), need
CC to be phosphorylated for its full activation.
CC -!- SUBUNIT: Interacts with GSK3B and FLII. Interacts with PDPK1 in a
CC phosphorylation-dependent manner. {ECO:0000269|PubMed:12054501,
CC ECO:0000269|PubMed:14604990, ECO:0000269|PubMed:16888620,
CC ECO:0000269|PubMed:19293151}.
CC -!- INTERACTION:
CC Q96BR1; Q96J02: ITCH; NbExp=5; IntAct=EBI-2801236, EBI-1564678;
CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle {ECO:0000250}. Early
CC endosome. Recycling endosome. Note=Endosomal localization is a
CC prerequisite for complete kinase activity. It is essential for its
CC colocalization with the kinase responsible for phosphorylating Ser-486
CC thus allowing PDPK1 phosphorylation of Thr-320 resulting in complete
CC activation of SGK3. Localized in vesicle-like structures and in the
CC early endosome. Colocalizes with SLC9A3/NHE3 in the recycling
CC endosomes.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96BR1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96BR1-2; Sequence=VSP_041903;
CC -!- TISSUE SPECIFICITY: Expressed in most tissues with highest levels in
CC pancreas, kidney liver, heart and brain and lower levels in lung,
CC placenta and skeletal muscle. Expression is higher in ER-positive
CC breast tumors than ER-negative breast tumors.
CC {ECO:0000269|PubMed:21084382}.
CC -!- INDUCTION: Induced by estrogen/ER in breast cancer cells.
CC {ECO:0000269|PubMed:21084382}.
CC -!- PTM: Activated by phosphorylation on Ser-486 by an unknown kinase (may
CC be mTORC2 but not confirmed), transforming it into a substrate for
CC PDPK1 which then phosphorylates it on Thr-320.
CC {ECO:0000269|PubMed:10548550, ECO:0000269|PubMed:14604990,
CC ECO:0000269|PubMed:16790420, ECO:0000269|PubMed:16888620}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF12758.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF169035; AAF12758.1; ALT_INIT; mRNA.
DR EMBL; AF085233; AAF27051.2; -; mRNA.
DR EMBL; AK074666; BAG51984.1; -; mRNA.
DR EMBL; AK291428; BAF84117.1; -; mRNA.
DR EMBL; AC011031; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC090154; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471068; EAW86919.1; -; Genomic_DNA.
DR EMBL; BC015326; AAH15326.1; -; mRNA.
DR CCDS; CCDS6195.1; -. [Q96BR1-1]
DR CCDS; CCDS6196.1; -. [Q96BR1-2]
DR RefSeq; NP_001028750.1; NM_001033578.2. [Q96BR1-1]
DR RefSeq; NP_001191102.1; NM_001204173.1. [Q96BR1-1]
DR RefSeq; NP_037389.4; NM_013257.4. [Q96BR1-1]
DR RefSeq; NP_733827.2; NM_170709.2. [Q96BR1-2]
DR PDB; 6EDX; X-ray; 2.01 A; A=10-125.
DR PDBsum; 6EDX; -.
DR AlphaFoldDB; Q96BR1; -.
DR SMR; Q96BR1; -.
DR BioGRID; 117195; 23.
DR ELM; Q96BR1; -.
DR IntAct; Q96BR1; 46.
DR MINT; Q96BR1; -.
DR STRING; 9606.ENSP00000379842; -.
DR BindingDB; Q96BR1; -.
DR ChEMBL; CHEMBL6186; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q96BR1; -.
DR GuidetoPHARMACOLOGY; 1536; -.
DR iPTMnet; Q96BR1; -.
DR PhosphoSitePlus; Q96BR1; -.
DR BioMuta; SGK3; -.
DR DMDM; 28558163; -.
DR EPD; Q96BR1; -.
DR jPOST; Q96BR1; -.
DR MassIVE; Q96BR1; -.
DR MaxQB; Q96BR1; -.
DR PaxDb; Q96BR1; -.
DR PeptideAtlas; Q96BR1; -.
DR PRIDE; Q96BR1; -.
DR ProteomicsDB; 76100; -. [Q96BR1-1]
DR ProteomicsDB; 76101; -. [Q96BR1-2]
DR Antibodypedia; 12043; 449 antibodies from 34 providers.
DR DNASU; 23678; -.
DR Ensembl; ENST00000345714.8; ENSP00000331816.5; ENSG00000104205.16. [Q96BR1-1]
DR Ensembl; ENST00000396596.2; ENSP00000379842.1; ENSG00000104205.16. [Q96BR1-1]
DR Ensembl; ENST00000520976.5; ENSP00000430691.1; ENSG00000104205.16. [Q96BR1-2]
DR Ensembl; ENST00000521198.7; ENSP00000430463.1; ENSG00000104205.16. [Q96BR1-1]
DR Ensembl; ENST00000522398.5; ENSP00000430256.1; ENSG00000104205.16. [Q96BR1-1]
DR GeneID; 100533105; -.
DR GeneID; 23678; -.
DR KEGG; hsa:100533105; -.
DR KEGG; hsa:23678; -.
DR MANE-Select; ENST00000521198.7; ENSP00000430463.1; NM_001033578.3; NP_001028750.1.
DR UCSC; uc003xwp.4; human. [Q96BR1-1]
DR CTD; 100533105; -.
DR CTD; 23678; -.
DR DisGeNET; 100533105; -.
DR DisGeNET; 23678; -.
DR GeneCards; SGK3; -.
DR HGNC; HGNC:10812; SGK3.
DR HPA; ENSG00000104205; Tissue enhanced (brain).
DR MIM; 607591; gene.
DR neXtProt; NX_Q96BR1; -.
DR OpenTargets; ENSG00000104205; -.
DR PharmGKB; PA35722; -.
DR VEuPathDB; HostDB:ENSG00000104205; -.
DR VEuPathDB; HostDB:ENSG00000288602; -.
DR eggNOG; KOG0598; Eukaryota.
DR eggNOG; KOG2101; Eukaryota.
DR GeneTree; ENSGT00940000153776; -.
DR HOGENOM; CLU_000288_63_48_1; -.
DR InParanoid; Q96BR1; -.
DR OMA; VEICEHE; -.
DR PhylomeDB; Q96BR1; -.
DR TreeFam; TF320906; -.
DR PathwayCommons; Q96BR1; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; Q96BR1; -.
DR SIGNOR; Q96BR1; -.
DR BioGRID-ORCS; 100533105; 14 hits in 198 CRISPR screens.
DR BioGRID-ORCS; 23678; 15 hits in 1090 CRISPR screens.
DR GeneWiki; SGK3; -.
DR Pharos; Q96BR1; Tchem.
DR PRO; PR:Q96BR1; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q96BR1; protein.
DR Bgee; ENSG00000104205; Expressed in pigmented layer of retina and 187 other tissues.
DR ExpressionAtlas; Q96BR1; baseline and differential.
DR Genevisible; Q96BR1; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005246; F:calcium channel regulator activity; TAS:UniProtKB.
DR GO; GO:0017081; F:chloride channel regulator activity; TAS:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0015459; F:potassium channel regulator activity; IBA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0017080; F:sodium channel regulator activity; TAS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR GO; GO:0001558; P:regulation of cell growth; TAS:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; TAS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; TAS:UniProtKB.
DR GO; GO:0051090; P:regulation of DNA-binding transcription factor activity; TAS:UniProtKB.
DR CDD; cd06870; PX_CISK; 1.
DR CDD; cd05604; STKc_SGK3; 1.
DR Gene3D; 3.30.1520.10; -; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR037900; CISK_PX.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001683; PX_dom.
DR InterPro; IPR036871; PX_dom_sf.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR037709; SGK3_dom.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00433; Pkinase_C; 1.
DR Pfam; PF00787; PX; 1.
DR SMART; SM00312; PX; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF64268; SSF64268; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50195; PX; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasmic vesicle;
KW Endosome; Kinase; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..496
FT /note="Serine/threonine-protein kinase Sgk3"
FT /id="PRO_0000086649"
FT DOMAIN 12..124
FT /note="PX"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00147"
FT DOMAIN 162..419
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 420..496
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 121..156
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 195..205
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT COMPBIAS 124..139
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 286
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 168..176
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 191
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 126
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9ERE3"
FT MOD_RES 129
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9ERE3"
FT MOD_RES 320
FT /note="Phosphothreonine; by PDPK1"
FT /evidence="ECO:0000269|PubMed:10548550,
FT ECO:0000269|PubMed:16790420"
FT MOD_RES 486
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:16790420,
FT ECO:0000269|PubMed:16888620"
FT VAR_SEQ 327..358
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_041903"
FT VARIANT 92
FT /note="A -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035636"
FT VARIANT 355
FT /note="L -> P (in dbSNP:rs750700898)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041076"
FT MUTAGEN 90
FT /note="R->A: Partially localized to the membrane."
FT /evidence="ECO:0000269|PubMed:16790420"
FT MUTAGEN 191
FT /note="K->M: Abolishes activity."
FT /evidence="ECO:0000269|PubMed:16790420"
FT MUTAGEN 486
FT /note="S->D: Increased activation."
FT /evidence="ECO:0000269|PubMed:10548550"
FT CONFLICT 54
FT /note="F -> V (in Ref. 2; AAF27051)"
FT /evidence="ECO:0000305"
FT CONFLICT 127
FT /note="D -> G (in Ref. 2; AAF27051)"
FT /evidence="ECO:0000305"
FT CONFLICT 187
FT /note="F -> V (in Ref. 2; AAF27051)"
FT /evidence="ECO:0000305"
FT CONFLICT 294
FT /note="L -> V (in Ref. 2; AAF27051)"
FT /evidence="ECO:0000305"
FT CONFLICT 387
FT /note="T -> R (in Ref. 2; AAF27051)"
FT /evidence="ECO:0000305"
FT STRAND 15..26
FT /evidence="ECO:0007829|PDB:6EDX"
FT STRAND 29..40
FT /evidence="ECO:0007829|PDB:6EDX"
FT STRAND 43..49
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 51..64
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 66..68
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 84..101
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 105..108
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 111..116
FT /evidence="ECO:0007829|PDB:6EDX"
FT HELIX 122..124
FT /evidence="ECO:0007829|PDB:6EDX"
SQ SEQUENCE 496 AA; 57108 MW; 76A6CCEB69006CF1 CRC64;
MQRDHTMDYK ESCPSVSIPS SDEHREKKKR FTVYKVLVSV GRSEWFVFRR YAEFDKLYNT
LKKQFPAMAL KIPAKRIFGD NFDPDFIKQR RAGLNEFIQN LVRYPELYNH PDVRAFLQMD
SPKHQSDPSE DEDERSSQKL HSTSQNINLG PSGNPHAKPT DFDFLKVIGK GSFGKVLLAK
RKLDGKFYAV KVLQKKIVLN RKEQKHIMAE RNVLLKNVKH PFLVGLHYSF QTTEKLYFVL
DFVNGGELFF HLQRERSFPE HRARFYAAEI ASALGYLHSI KIVYRDLKPE NILLDSVGHV
VLTDFGLCKE GIAISDTTTT FCGTPEYLAP EVIRKQPYDN TVDWWCLGAV LYEMLYGLPP
FYCRDVAEMY DNILHKPLSL RPGVSLTAWS ILEELLEKDR QNRLGAKEDF LEIQNHPFFE
SLSWADLVQK KIPPPFNPNV AGPDDIRNFD TAFTEETVPY SVCVSSDYSI VNASVLEADD
AFVGFSYAPP SEDLFL
