RBCC Red Blood Cell Collection

AKT3 (PKBG) [Confidence: low (only semi-automatic identification from reviews)]
RAC-gamma serine/threonine-protein kinase; 2.7.11.1 (Protein kinase Akt-3; Protein kinase B gamma; PKB gamma; RAC-PK-gamma; STK-2)

UniProt Q9Y243
ID AKT3_HUMAN Reviewed; 479 AA.
AC Q9Y243; Q0VAA6; Q5VTI1; Q5VTI2; Q96QV3; Q9UFP5;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1999, sequence version 1.
DT 22-JAN-2014, entry version 147.
DE RecName: Full=RAC-gamma serine/threonine-protein kinase;
DE EC=2.7.11.1;
DE AltName: Full=Protein kinase Akt-3;
DE AltName: Full=Protein kinase B gamma;
DE Short=PKB gamma;
DE AltName: Full=RAC-PK-gamma;
DE AltName: Full=STK-2;
GN Name=AKT3; Synonyms=PKBG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTAGENESIS.
RX PubMed=10092583; DOI=10.1074/jbc.274.14.9133;
RA Brodbeck D., Cron P., Hemmings B.A.;
RT "A human protein kinase B gamma with regulatory phosphorylation sites
RT in the activation loop and in the C-terminal hydrophobic domain.";
RL J. Biol. Chem. 274:9133-9136(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10208883; DOI=10.1006/bbrc.1999.0559;
RA Nakatani K., Sakaue H., Thompson D.A., Weigel R.J., Roth R.A.;
RT "Identification of a human Akt3 (protein kinase B gamma) which
RT contains the regulatory serine phosphorylation site.";
RL Biochem. Biophys. Res. Commun. 257:906-910(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=10491192; DOI=10.1046/j.1432-1327.1999.00774.x;
RA Masure S., Haefner B., Wesselink J.-J., Hoefnagel E., Mortier E.,
RA Verhasselt P., Tuytelaars A., Gordon R., Richardson A.;
RT "Molecular cloning, expression and characterization of the human
RT serine/threonine kinase Akt-3.";
RL Eur. J. Biochem. 265:353-360(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Li X., Yu L., Huang H., Zhang M., Zhao Y., Zhao S.;
RT "Cloning of a novel human cDNA, STK-2, which encodes a rat serine-
RT threonine protein kinase (STK) homolog.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND MUTAGENESIS OF
RP THR-305 AND THR-447.
RX PubMed=11387345; DOI=10.1074/jbc.M104633200;
RA Brodbeck D., Hill M.M., Hemmings B.A.;
RT "Two splice variants of PKB gamma have different regulatory capacity
RT depending on the presence or absence of the regulatory phosphorylation
RT site Ser-472 in the C-terminal hydrophobic domain.";
RL J. Biol. Chem. 276:29550-29558(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP CHARACTERIZATION, AND PHOSPHORYLATION AT THR-305 BY PDPK1.
RX PubMed=9512493;
RA Walker K.S., Deak M., Paterson A., Hudson K., Cohen P., Alessi D.R.;
RT "Activation of protein kinase B beta and gamma isoforms by insulin in
RT vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro:
RT comparison with protein kinase B alpha.";
RL Biochem. J. 331:299-308(1998).
RN [11]
RP PHOSPHORYLATION AT SER-472.
RX PubMed=12162751; DOI=10.1021/bi026065r;
RA Hodgkinson C.P., Sale E.M., Sale G.J.;
RT "Characterization of PDK2 activity against protein kinase B gamma.";
RL Biochemistry 41:10351-10359(2002).
RN [12]
RP INTERACTION WITH TCL1A.
RX PubMed=11707444; DOI=10.1074/jbc.M107069200;
RA Laine J., Kuenstle G., Obata T., Noguchi M.;
RT "Differential regulation of Akt kinase isoforms by the members of the
RT TCL1 oncogene family.";
RL J. Biol. Chem. 277:3743-3751(2002).
RN [13]
RP INTERACTION WITH TCL1A.
RX PubMed=11839817; DOI=10.1128/MCB.22.5.1513-1525.2002;
RA Kuenstle G., Laine J., Pierron G., Kagami S., Nakajima H., Hoh F.,
RA Roumestand C., Stern M.H., Noguchi M.;
RT "Identification of Akt association and oligomerization domains of the
RT Akt kinase coactivator TCL1.";
RL Mol. Cell. Biol. 22:1513-1525(2002).
RN [14]
RP INVOLVEMENT IN TUMORS.
RX PubMed=15466193; DOI=10.1158/0008-5472.CAN-04-1399;
RA Stahl J.M., Sharma A., Cheung M., Zimmerman M., Cheng J.Q.,
RA Bosenberg M.W., Kester M., Sandirasegarane L., Robertson G.P.;
RT "Deregulated Akt3 activity promotes development of malignant
RT melanoma.";
RL Cancer Res. 64:7002-7010(2004).
RN [15]
RP INVOLVEMENT IN CANCER.
RX PubMed=17178867; DOI=10.1158/0008-5472.CAN-06-1968;
RA Cristiano B.E., Chan J.C., Hannan K.M., Lundie N.A., Marmy-Conus N.J.,
RA Campbell I.G., Phillips W.A., Robbie M., Hannan R.D., Pearson R.B.;
RT "A specific role for AKT3 in the genesis of ovarian cancer through
RT modulation of G(2)-M phase transition.";
RL Cancer Res. 66:11718-11725(2006).
RN [16]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16540465; DOI=10.1074/jbc.M601384200;
RA Zhang X., Zhang S., Yamane H., Wahl R., Ali A., Lofgren J.A.,
RA Kendall R.L.;
RT "Kinetic mechanism of AKT/PKB enzyme family.";
RL J. Biol. Chem. 281:13949-13956(2006).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [18]
RP FUNCTION.
RX PubMed=18524868; DOI=10.1096/fj.08-106468;
RA Wright G.L., Maroulakou I.G., Eldridge J., Liby T.L., Sridharan V.,
RA Tsichlis P.N., Muise-Helmericks R.C.;
RT "VEGF stimulation of mitochondrial biogenesis: requirement of AKT3
RT kinase.";
RL FASEB J. 22:3264-3275(2008).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP UBIQUITINATION BY TTC3.
RX PubMed=20059950; DOI=10.1016/j.devcel.2009.09.007;
RA Suizu F., Hiramuki Y., Okumura F., Matsuda M., Okumura A.J.,
RA Hirata N., Narita M., Kohno T., Yokota J., Bohgaki M., Obuse C.,
RA Hatakeyama S., Obata T., Noguchi M.;
RT "The E3 ligase TTC3 facilitates ubiquitination and degradation of
RT phosphorylated Akt.";
RL Dev. Cell 17:800-810(2009).
RN [21]
RP INTERACTION WITH TRAF6.
RX PubMed=19713527; DOI=10.1126/science.1175065;
RA Yang W.-L., Wang J., Chan C.-H., Lee S.-W., Campos A.D., Lamothe B.,
RA Hur L., Grabiner B.C., Lin X., Darnay B.G., Lin H.-K.;
RT "The E3 ligase TRAF6 regulates Akt ubiquitination and activation.";
RL Science 325:1134-1138(2009).
RN [22]
RP SUBCELLULAR LOCATION.
RX PubMed=20018949; DOI=10.1152/ajpcell.00375.2009;
RA Santi S.A., Lee H.;
RT "The Akt isoforms are present at distinct subcellular locations.";
RL Am. J. Physiol. 298:C580-C591(2010).
RN [23]
RP INVOLVEMENT IN TUMORS.
RX PubMed=20167810; DOI=10.1093/neuonc/nop026;
RA Mure H., Matsuzaki K., Kitazato K.T., Mizobuchi Y., Kuwayama K.,
RA Kageji T., Nagahiro S.;
RT "Akt2 and Akt3 play a pivotal role in malignant gliomas.";
RL Neuro-oncol. 12:221-232(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP FUNCTION.
RX PubMed=21191416; DOI=10.1038/jid.2010.361;
RA Moriya C., Jinnin M., Yamane K., Maruo K., Muchemwa F.C., Igata T.,
RA Makino T., Fukushima S., Ihn H.;
RT "Expression of matrix metalloproteinase-13 is controlled by IL-13 via
RT PI3K/Akt3 and PKC-delta in normal human dermal fibroblasts.";
RL J. Invest. Dermatol. 131:655-661(2011).
RN [26]
RP REVIEW ON FUNCTION.
RX PubMed=21620960; DOI=10.1016/j.cellsig.2011.05.004;
RA Hers I., Vincent E.E., Tavare J.M.;
RT "Akt signalling in health and disease.";
RL Cell. Signal. 23:1515-1527(2011).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.46 ANGSTROMS) OF 1-118.
RA Vollmar M., Wang J., Zhang Y., Elkins J.M., Burgess-Brown N.,
RA Chaikuad A., Pike A.C.W., Von Delft F., Bountra C., Arrowsmith C.H.,
RA Weigelt J., Edwards A., Knapp S.;
RT "The crystal structure of the PH domain of human Akt3 protein
RT kinase.";
RL Submitted (DEC-2009) to the PDB data bank.
RN [28]
RP VARIANT [LARGE SCALE ANALYSIS] ARG-171.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [29]
RP VARIANT MELANOMA LYS-17, AND CHARACTERIZATION OF VARIANT MELANOMA
RP LYS-17.
RX PubMed=18813315; DOI=10.1038/sj.bjc.6604637;
RA Davies M.A., Stemke-Hale K., Tellez C., Calderone T.L., Deng W.,
RA Prieto V.G., Lazar A.J., Gershenwald J.E., Mills G.B.;
RT "A novel AKT3 mutation in melanoma tumours and cell lines.";
RL Br. J. Cancer 99:1265-1268(2008).
RN [30]
RP VARIANTS MPPH SER-229 AND TRP-465.
RX PubMed=22729224; DOI=10.1038/ng.2331;
RA Riviere J.B., Mirzaa G.M., O'Roak B.J., Beddaoui M., Alcantara D.,
RA Conway R.L., St-Onge J., Schwartzentruber J.A., Gripp K.W.,
RA Nikkel S.M., Worthylake T., Sullivan C.T., Ward T.R., Butler H.E.,
RA Kramer N.A., Albrecht B., Armour C.M., Armstrong L., Caluseriu O.,
RA Cytrynbaum C., Drolet B.A., Innes A.M., Lauzon J.L., Lin A.E.,
RA Mancini G.M., Meschino W.S., Reggin J.D., Saggar A.K.,
RA Lerman-Sagie T., Uyanik G., Weksberg R., Zirn B., Beaulieu C.L.,
RA Majewski J., Bulman D.E., O'Driscoll M., Shendure J., Graham J.M. Jr.,
RA Boycott K.M., Dobyns W.B.;
RT "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA
RT cause a spectrum of related megalencephaly syndromes.";
RL Nat. Genet. 44:934-940(2012).
RN [31]
RP VARIANT MPPH LYS-17.
RX PubMed=22729223; DOI=10.1038/ng.2329;
RA Lee J.H., Huynh M., Silhavy J.L., Kim S., Dixon-Salazar T.,
RA Heiberg A., Scott E., Bafna V., Hill K.J., Collazo A., Funari V.,
RA Russ C., Gabriel S.B., Mathern G.W., Gleeson J.G.;
RT "De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway
RT cause hemimegalencephaly.";
RL Nat. Genet. 44:941-945(2012).
RN [32]
RP VARIANT MPPH LYS-17.
RX PubMed=22500628; DOI=10.1016/j.neuron.2012.03.010;
RA Poduri A., Evrony G.D., Cai X., Elhosary P.C., Beroukhim R.,
RA Lehtinen M.K., Hills L.B., Heinzen E.L., Hill A., Hill R.S.,
RA Barry B.J., Bourgeois B.F., Riviello J.J., Barkovich A.J., Black P.M.,
RA Ligon K.L., Walsh C.A.;
RT "Somatic activation of AKT3 causes hemispheric developmental brain
RT malformations.";
RL Neuron 74:41-48(2012).
CC -!- FUNCTION: AKT3 is one of 3 closely related serine/threonine-
CC protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and
CC which regulate many processes including metabolism, proliferation,
CC cell survival, growth and angiogenesis. This is mediated through
CC serine and/or threonine phosphorylation of a range of downstream
CC substrates. Over 100 substrate candidates have been reported so
CC far, but for most of them, no isoform specificity has been
CC reported. AKT3 is the least studied AKT isoform. It plays an
CC important role in brain development and is crucial for the
CC viability of malignant glioma cells. AKT3 isoform may also be the
CC key molecule in up-regulation and down-regulation of MMP13 via
CC IL13. Required for the coordination of mitochondrial biogenesis
CC with growth factor-induced increases in cellular energy demands.
CC Down-regulation by RNA interference reduces the expression of the
CC phosphorylated form of BAD, resulting in the induction of caspase-
CC dependent apoptosis.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Two specific sites, one in the kinase domain
CC (Thr-305) and the other in the C-terminal regulatory region (Ser-
CC 472), need to be phosphorylated for its full activation (By
CC similarity). IGF-1 leads to the activation of AKT3, which may play
CC a role in regulating cell survival.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=87.9 uM for ATP (for purified and in vitro activated AKT3);
CC KM=12.4 uM for peptide substrate (for purified and in vitro
CC activated AKT3);
CC KM=118.7 uM for ATP (for recombinant myristoylated AKT3
CC expressed and immunoprecipitated from Rat-1 cells);
CC KM=2.3 uM for peptide substrate (for recombinant myristoylated
CC AKT3 expressed and immunoprecipitated from Rat-1 cells);
CC -!- SUBUNIT: Interacts (via PH domain) with TCL1A; this enhances AKT3
CC phosphorylation and activation. Interacts with TRAF6.
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Membrane; Peripheral
CC membrane protein. Note=Membrane-associated after cell stimulation
CC leading to its translocation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PKB gamma;
CC IsoId=Q9Y243-1; Sequence=Displayed;
CC Name=2; Synonyms=PKB gamma 1;
CC IsoId=Q9Y243-2; Sequence=VSP_004947;
CC -!- TISSUE SPECIFICITY: In adult tissues, it is highly expressed in
CC brain, lung and kidney, but weakly in heart, testis and liver. In
CC fetal tissues, it is highly expressed in heart, liver and brain
CC and not at all in kidney.
CC -!- DOMAIN: Binding of the PH domain to the phosphatidylinositol 3-
CC kinase alpha (PI(3)K) results in its targeting to the plasma
CC membrane.
CC -!- PTM: Phosphorylation on Thr-305 and Ser-472 is required for full
CC activity (By similarity).
CC -!- PTM: Ubiquitinated. When fully phosphorylated and translocated
CC into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed
CC by TTC3, leading to its degradation by the proteasome.
CC -!- PTM: O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating
CC phosphorylation at Thr-305 via disrupting the interaction between
CC AKT and PDK1 (By similarity).
CC -!- DISEASE: Note=AKT3 is a key modulator of several tumors like
CC melanoma, glioma and ovarian cancer. Active AKT3 increases
CC progressively during melanoma tumor progression with highest
CC levels present in advanced-stage metastatic melanomas. Promotes
CC melanoma tumorigenesis by decreasing apoptosis. Plays a key role
CC in the genesis of ovarian cancers through modulation of G2/M phase
CC transition. With AKT2, plays a pivotal role in the biology of
CC glioblastoma.
CC -!- DISEASE: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus
CC syndrome (MPPH) [MIM:603387]: A syndrome characterized by
CC megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may
CC also be seen. There is considerable phenotypic similarity between
CC this disorder and the megalencephaly-capillary malformation
CC syndrome. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. RAC subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- CAUTION: In light of strong homologies in the primary amino acid
CC sequence, the 3 AKT kinases were long surmised to play redundant
CC and overlapping roles. More recent studies has brought into
CC question the redundancy within AKT kinase isoforms and instead
CC pointed to isoform specific functions in different cellular events
CC and diseases. AKT1 is more specifically involved in cellular
CC survival pathways, by inhibiting apoptotic processes; whereas AKT2
CC is more specific for the insulin receptor signaling pathway.
CC Moreover, while AKT1 and AKT2 are often implicated in many aspects
CC of cellular transformation, the 2 isoforms act in a complementary
CC opposing manner. The role of AKT3 is less clear, though it appears
CC to be predominantly expressed in brain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/AKT3ID615ch1q44.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF124141; AAD29089.1; -; mRNA.
DR EMBL; AF135794; AAD24196.1; -; mRNA.
DR EMBL; AF085234; AAL40392.1; -; mRNA.
DR EMBL; AJ245709; CAB53537.1; -; mRNA.
DR EMBL; AL117525; CAB55977.1; ALT_TERM; mRNA.
DR EMBL; AY005799; AAF91073.1; -; mRNA.
DR EMBL; AL591721; CAH71866.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH71866.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH71866.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH71866.1; JOINED; Genomic_DNA.
DR EMBL; AL591721; CAH71867.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH71867.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH71867.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH71867.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH72891.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH72891.1; JOINED; Genomic_DNA.
DR EMBL; AL591721; CAH72891.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH72891.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH72892.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH72892.1; JOINED; Genomic_DNA.
DR EMBL; AL591721; CAH72892.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH72892.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH73072.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH73072.1; JOINED; Genomic_DNA.
DR EMBL; AL591721; CAH73072.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH73072.1; JOINED; Genomic_DNA.
DR EMBL; AL662889; CAH73073.1; -; Genomic_DNA.
DR EMBL; AC096539; CAH73073.1; JOINED; Genomic_DNA.
DR EMBL; AL591721; CAH73073.1; JOINED; Genomic_DNA.
DR EMBL; AL592151; CAH73073.1; JOINED; Genomic_DNA.
DR EMBL; CH471148; EAW77093.1; -; Genomic_DNA.
DR EMBL; CH471148; EAW77094.1; -; Genomic_DNA.
DR EMBL; BC121154; AAI21155.1; -; mRNA.
DR PIR; A59380; A59380.
DR PIR; T17287; T17287.
DR RefSeq; NP_001193658.1; NM_001206729.1.
DR RefSeq; NP_005456.1; NM_005465.4.
DR RefSeq; NP_859029.1; NM_181690.2.
DR RefSeq; XP_005273051.1; XM_005272994.1.
DR RefSeq; XP_005273052.1; XM_005272995.1.
DR UniGene; Hs.498292; -.
DR PDB; 2X18; X-ray; 1.46 A; A/B/C/D/E/F/G/H=1-118.
DR PDBsum; 2X18; -.
DR ProteinModelPortal; Q9Y243; -.
DR SMR; Q9Y243; 3-476.
DR IntAct; Q9Y243; 2.
DR MINT; MINT-222821; -.
DR STRING; 9606.ENSP00000263826; -.
DR BindingDB; Q9Y243; -.
DR ChEMBL; CHEMBL2111353; -.
DR GuidetoPHARMACOLOGY; 2286; -.
DR PhosphoSite; Q9Y243; -.
DR DMDM; 12643943; -.
DR PaxDb; Q9Y243; -.
DR PRIDE; Q9Y243; -.
DR DNASU; 10000; -.
DR Ensembl; ENST00000263826; ENSP00000263826; ENSG00000117020.
DR Ensembl; ENST00000336199; ENSP00000336943; ENSG00000117020.
DR Ensembl; ENST00000366539; ENSP00000355497; ENSG00000117020.
DR Ensembl; ENST00000366540; ENSP00000355498; ENSG00000117020.
DR GeneID; 10000; -.
DR KEGG; hsa:10000; -.
DR UCSC; uc001iab.2; human.
DR CTD; 10000; -.
DR GeneCards; GC01M243653; -.
DR HGNC; HGNC:393; AKT3.
DR HPA; CAB013090; -.
DR HPA; HPA026441; -.
DR MIM; 603387; phenotype.
DR MIM; 611223; gene.
DR neXtProt; NX_Q9Y243; -.
DR Orphanet; 99802; Hemimegalencephaly.
DR Orphanet; 83473; Megalencephaly - polymicrogyria - post-axial polydactyly - hydrocephalus.
DR PharmGKB; PA24686; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; Q9Y243; -.
DR KO; K04456; -.
DR OMA; DTPEEXT; -.
DR OrthoDB; EOG7Q5HCW; -.
DR PhylomeDB; Q9Y243; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9Y243; -.
DR ChiTaRS; AKT3; human.
DR GeneWiki; AKT3; -.
DR GenomeRNAi; 10000; -.
DR NextBio; 37765; -.
DR PRO; PR:Q9Y243; -.
DR ArrayExpress; Q9Y243; -.
DR Bgee; Q9Y243; -.
DR CleanEx; HS_AKT3; -.
DR Genevestigator; Q9Y243; -.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0000002; P:mitochondrial genome maintenance; IMP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IMP:UniProtKB.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00433; Pkinase_C; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS50003; PH_DOMAIN; 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; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Disease mutation; Disulfide bond;
KW Glycoprotein; Kinase; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 479 RAC-gamma serine/threonine-protein
FT kinase.
FT /FTId=PRO_0000085611.
FT DOMAIN 5 107 PH.
FT DOMAIN 148 405 Protein kinase.
FT DOMAIN 406 479 AGC-kinase C-terminal.
FT NP_BIND 154 162 ATP (By similarity).
FT ACT_SITE 271 271 Proton acceptor (By similarity).
FT BINDING 177 177 ATP (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 305 305 Phosphothreonine; by PDPK1.
FT MOD_RES 472 472 Phosphoserine; by PKC/PRKCZ.
FT CARBOHYD 302 302 O-linked (GlcNAc) (By similarity).
FT CARBOHYD 309 309 O-linked (GlcNAc) (By similarity).
FT DISULFID 59 76 By similarity.
FT DISULFID 293 307 By similarity.
FT VAR_SEQ 452 479 YDEDGMDCMDNERRPHFPQFSYSASGRE -> CQQSDCGML
FT GNWKK (in isoform 2).
FT /FTId=VSP_004947.
FT VARIANT 17 17 E -> K (in MPPH and melanoma; results in
FT activation of AKT).
FT /FTId=VAR_065830.
FT VARIANT 171 171 G -> R (in a glioblastoma multiforme
FT sample; somatic mutation).
FT /FTId=VAR_040358.
FT VARIANT 229 229 N -> S (in MPPH).
FT /FTId=VAR_069260.
FT VARIANT 465 465 R -> W (in MPPH; disease phenotype
FT overlaps with megalencephaly-capillary
FT malformation syndrome).
FT /FTId=VAR_069261.
FT MUTAGEN 305 305 T->A: No activation after pervanadate
FT treatment.
FT MUTAGEN 305 305 T->D: 2-fold increase of phosphorylation
FT steady state level, no activation after
FT pervanadate treatment.
FT MUTAGEN 447 447 T->A: No effect.
FT MUTAGEN 447 447 T->D: No effect.
FT MUTAGEN 472 472 S->A: 67% decrease of activity after
FT pervanadate treatment.
FT MUTAGEN 472 472 S->D: 1.4-fold increase of
FT phosphorylation steady state level, 50%
FT decrease of activity after pervanadate
FT treatment.
FT CONFLICT 279 279 L -> R (in Ref. 9; AAI21155).
FT STRAND 6 15
FT STRAND 17 30
FT STRAND 33 41
FT HELIX 44 46
FT STRAND 51 55
FT STRAND 60 64
FT STRAND 66 68
FT STRAND 71 75
FT TURN 80 82
FT STRAND 84 88
FT HELIX 92 113
SQ SEQUENCE 479 AA; 55775 MW; F08BDDE6502E78FB CRC64;
MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP LNNFSVAKCQ
LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE AIQAVADRLQ RQEEERMNCS
PTSQIDNIGE EEMDASTTHH KRKTMNDFDY LKLLGKGTFG KVILVREKAS GKYYAMKILK
KEVIIAKDEV AHTLTESRVL KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE
RVFSEDRTRF YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA
ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD HEKLFELILM
EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM RHSFFSGVNW QDVYDKKLVP
PFKPQVTSET DTRYFDEEFT AQTITITPPE KYDEDGMDCM DNERRPHFPQ FSYSASGRE
//

MIM 603387
*RECORD*
*FIELD* NO
603387
*FIELD* TI
#603387 MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME;
MPPH
;;MEGALENCEPHALY, POLYMICROGYRIA, MEGA CORPUS CALLOSUM SYNDROME;;
read moreMEG-PMG-MEGACC SYNDROME;;
MEGALENCEPHALY, MEGA CORPUS CALLOSUM, AND COMPLETE LACK OF MOTOR DEVELOPMENT
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH)
can be caused by heterozygous mutation in the PIK3R2 gene (603157) on
chromosome 19p13 or in the AKT3 gene (611223) on chromosome 1q43-q44.

Somatic mutations in the AKT3 gene and in the PIK3CA gene (171834) have
also been identified in MPPH.

DESCRIPTION

This disorder comprises megalencephaly, hydrocephalus, and
polymicrogyria; polydactyly may also be seen. There is considerable
phenotypic similarity between this disorder and the
megalencephaly-capillary malformation syndrome (MCAP; 602501) (summary
by Gripp et al., 2009).

CLINICAL FEATURES

Gohlich-Ratmann et al. (1998) reported 3 sporadic cases of in
utero-onset megalencephaly. The children were born to healthy
nonconsanguineous parents after uneventful pregnancies. Head
circumferences were just above the 97th centile at birth in 2 patients,
2 cm above the 97th centile in 1 patient, and subsequently increased to
4.5 to 6.5 cm above the 97th centile at age 5 years. All patients
completely lacked motor and speech development and showed very little
intellectual progress. There was a distinctive facial aspect with
frontal bossing, low nasal bridge, and large eyes, but no cutaneous
abnormalities and no signs of other organ involvement. Magnetic
resonance imaging showed bilateral megalencephaly with a broad corpus
callosum, enlarged white matter, and focally thick gray matter,
resulting in pachygyric appearance of the cortex. Formation of the
frontoparietal operculum was incomplete, and the Sylvian fissures were
wide. Gohlich-Ratmann et al. (1998) knew of no reports of similar cases.
On review of the MRI figures in the paper by Gohlich-Ratmann et al.
(1998), Mirzaa et al. (2004) concluded that the cortical dysplasia
suggested polymicrogyria rather than typical pachygyria, a point with
which the authors of the 1998 paper agreed. Mirzaa et al. (2004) thus
suggested the designation megalencephaly-polymicrogyria-mega-corpus
callosum (MEG-PMG-MegaCC) syndrome. Postaxial polydactyly was also seen
in the patients reported by Mirzaa et al. (2004).

Dagli et al. (2008) reported a female infant with a phenotype similar to
that described by Gohlich-Ratmann et al. (1998). At birth, she had
macrocephaly, hypotonia, frontal bossing, depressed nasal bridge, and
normal brain MRI. Features noted later included open anterior fontanel,
wide palpebral fissures, ptosis, and profound mental retardation with no
psychomotor development. Brain MRI at age 15 months showed bilateral
megalencephaly with generalized thickening of the cortex, severe
enlargement of the corpus callosum, and a cavum septum pellucidum. There
was abnormal sulcation, which may be seen with polymicrogyria. The
ventricles were normal in size, and the Sylvian fissures were not wide.
The patient died at home at 21 months of age from respiratory
complications associated with a flu-like illness.

Hengst et al. (2010) reported a 3-year-old girl who was born with
macrocephaly and showed hypotonia, reduced spontaneous movements, and
severely delayed motor development. Brain MRI at age 8 months showed
extensive polymicrogyria sparing the midline cortical structures and the
visual cortex, a markedly enlarged corpus callosum, and megalencephaly
of the hemispheres and cerebellum. There was increased diameter of the
internal cerebral vein, the vein of Galen, and the straight sinus. By
age 2 years, she had learned to control her head for a short time and to
roll around, but could not sit or grasp. She had hypotonia, with
salivation, mental retardation, and lack of speech. There was no facial
dysmorphism and she did not have seizures. Hengst et al. (2010)
suggested the term 'megalencephaly-mega corpus callosum-motor
retardation syndrome (MMM)' as a more accurate designation.

DIAGNOSIS

Mirzaa et al. (2012) reviewed the phenotypic features of 42 patients
with a megalencephalic syndrome in an attempt to clarify and simplify
the categorization and diagnosis of these disorders. Statistical
analysis of particular features yielded 2 main groups: 21 patients with
a vascular malformation consistent with MCAP and 19 with no vascular
malformation consistent with MPPH; 2 patients were in an overlap group.
Vascular malformations were significantly associated with syndactyly and
somatic overgrowth at birth, and lack of vascular malformations was
associated with polydactyly. The various features were assigned to 5
major classes of developmental abnormalities. Both MCAP and MPPH had (1)
megalencephaly and variable somatic overgrowth (particularly in MCAP);
(2) distal limb malformations, syndactyly being more associated with
MCAP and polydactyly with MPPH; and (3) similar cortical brain
malformations (mainly polymicrogyria). In addition, MCAP included (4)
developmental vascular abnormalities and (5) occasional connective
tissue dysplasia, such as hyperelasticity or thick skin. MPPH lacks
vascular malformations, connective tissue dysplasia, and heterotopia.
Based on these findings, Mirzaa et al. (2012) proposed diagnostic
criteria for the MCAP and MPPH syndromes, and postulated that the 2
disorders represent different, although overlapping, syndromes that may
be caused by different genes involved in the same biologic pathway.

MOLECULAR GENETICS

Riviere et al. (2012) performed exome sequencing in the oldest of 3
affected sibs with MPPH and identified a heterozygous mutation in the
PIK3R2 gene (G373R; 603157.0001), which encodes the p85B regulatory
subunit of class IA PI3K. Sanger sequencing confirmed the presence of
the mutation in all 3 affected sibs and its absence in the saliva and
blood of both parents and the unaffected sister, showing germline
mosaicism in 1 parent. Sequencing of the PIK3R2 gene in 40 individuals
with megalencephaly identified the same nucleotide change in 10
additional subjects with MPPH, and this mutation was shown to be de novo
in all subjects for whom parental DNA was available. The mutation
occurred at a CpG dinucleotide, which might explain its recurrence.

Riviere et al. (2012) performed exome sequencing in an individual with
clinical features overlapping MPPH and megalencephaly-capillary
malformation-polymicrogyria syndrome (MCAP; 602501) and his parents and
identified a de novo mutation in the AKT3 gene (R465W; 611223.0001).
Sanger sequencing of the AKT3 gene in another 40 individuals with
megalencephaly (many with asymmetric brain enlargement, and several
diagnosed with hemimegalencephaly) identified a different de novo
mutation in this gene in 1 individual with MPPH (N229S; 611223.0002).
Riviere et al. (2012) suggested that the AKT3 gene is a rare cause of
megalencephaly (p = 0.002, calculated as the likelihood of observing a
second de novo mutation in the AKT3 gene).

In 8 samples of brain tissue from individuals with hemimegalencephaly
(HME), Poduri et al. (2012) identified somatic duplications of
chromosome 1q encompassing the AKT3 gene in 2. Sequencing of the AKT3
gene in the other 6 samples identified 1 with a known activating
mutation (E17K; 611223.0003); the mutation was not detectable in blood
from this patient.

Lee et al. (2012) performed whole-exome sequencing on brain and
peripheral blood DNA from 5 HME cases and identified 3 missense
mutations: one in the PIK3CA gene (E545K; 171834.0003), one in the AKT3
gene (E17K; 611223.0003), and one in the MTOR gene (C1483Y). The
individual with the MTOR gene mutation also carried a diagnosis of
hypomelanosis of Ito (300337). Lee et al. (2012) then used a modified
single base-extension protocol followed by mass spectrometry analysis to
detect somatic mutations at a frequency as low as 3% in genetically
heterogeneous samples. Reanalysis of the same DNA samples used for
whole-exome sequencing again showed the absence of the mutant allele in
blood but its presence in the brain, with similar mutation burden as
that detected with Illumina sequencing. These somatic mutations were
detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample.
Using the same technology, Lee et al. (2012) screened for these
mutations in 15 other HME cases and identified 3 additional cases
carrying the PIK3CA E545K variant, each with a mutation burden of about
30%. One of these individuals had hypertrophic regions in the right hand
and foot.

*FIELD* RF
1. Dagli, A. I.; Stalker, H. J.; Williams, C. A.: A patient with
the syndrome of megalencephaly, mega corpus callosum and complete
lack of motor development. Am. J. Med. Genet. 146A: 204-207, 2008.

2. Gohlich-Ratmann, G.; Baethmann, M.; Lorenz, P.; Gartner, J.; Goebel,
H. H.; Engelbrecht, V.; Christen, H.-J.; Lenard, H.-G.; Voit, T.:
Megalencephaly, mega corpus callosum, and complete lack of motor development:
a previously undescribed syndrome. Am. J. Med. Genet. 79: 161-167,
1998.

3. Gripp, K. W.; Hopkins, E.; Vinkler, C.; Lev, D.; Malinger, G.;
Lerman-Sagie, T.; Dobyns, W. B.: Significant overlap and possible
identity of macrocephaly capillary malformation and megalencephaly
polymicrogyria-polydactyly hydrocephalus syndromes. Am. J. Med. Genet. 149A:
868-876, 2009.

4. Hengst, M.; Tucke, J.; Zerres, K.; Blaum, M.; Hausler, M.: Megalencephaly,
mega corpus callosum, and complete lack of motor development: delineation
of a rare syndrome. Am. J. Med. Genet. 152A: 2360-2364, 2010.

5. Lee, J. H.; Huynh, M.; Silhavy, J. L.; Kim, S.; Dixon-Salazar,
T.; Heiberg, A.; Scott, E.; Bafna, V.; Hill, K. J.; Collazo, A.; Funari,
V.; Russ, C.; Gabriel, S. B.; Mathern, G. W.; Gleeson, J. G.: De
novo somatic mutations in components of the PI3K-AKT3-mTOR pathway
cause hemimegalencephaly. Nature Genet. 44: 941-945, 2012.

6. Mirzaa, G.; Dodge, N. N.; Glass, I.; Day, C.; Gripp, K.; Nicholson,
L.; Straub, V.; Voit, T.; Dobyns, W. B.: Megalencephaly and perisylvian
polymicrogyria with postaxial polydactyly and hydrocephalus: a rare
brain malformation syndrome associated with mental retardation and
seizures. Neuropediatrics 35: 353-359, 2004.

7. Mirzaa, G. M.; Conway, R. L.; Gripp, K. W.; Lerman-Sagie, T.; Siegel,
D. H.; deVries, L. S.; Lev, D.; Kramer, N.; Hopkins, E.; Graham, J.
M., Jr.; Dobyns, W. B.: Megalencephaly-capillary malformation (MCAP)
and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH)
syndromes: two closely related disorders of brain overgrowth and abnormal
brain and body morphogenesis. Am. J. Med. Genet. 158A: 269-291,
2012.

8. Poduri, A.; Evrony, G. D.; Cai, X.; Elhosary, P. C.; Beroukhim,
R.; Lehtinen, M. K.; Hills, L. B.; Heinzen, E. L.; Hill, A.; Hill,
R. S.; Barry, B. J.; Bourgeois, B. F. D.; Riviello, J. J.; Barkovich,
A. J.; Black, P. M.; Ligon, K. L.; Walsh, C. A.: Somatic activation
of AKT3 causes hemispheric developmental brain malformations. Neuron 74:
41-48, 2012.

9. Riviere, J.-B.; Mirzaa, G. M.; O'Roak, B. J.; Beddaoui, M.; Alcantara,
D.; Conway, R. L.; St-Onge, J.; Schwartzentruber, J. A.; Gripp, K.
W.; Nikkel, S. M.; Worthylake, T.; Sullivan, C. T.; and 29 others
: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA
cause a spectrum of related megalencephaly syndromes. Nature Genet. 44:
934-940, 2012.

10. Riviere, J.-B.; Mirzaa, G. M.; O'Roak, B. J.; Beddaoui, M.; Alcantara,
D.; Conway, R. L.; St-Onge, J.; Schwartzentruber, J. A.; Gripp, K.
W.; Nikkel, S. M.; Worthylake, T.; Sullivan, C. T.; and 29 others
: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA
cause a spectrum of related megalencephaly syndromes. Nature Genet. 44:
934-940, 2012.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Small birth length

HEAD AND NECK:
[Head];
Macrocephaly;
[Face];
Frontal bossing;
[Eyes];
Large eyes;
Blindness;
Pale optic nerves;
Wide palpebral fissures;
Eyelid ptosis;
[Nose];
Low bridge;
[Mouth];
Tent-shaped mouth;
Prominent philtral groove;
Submucous cleft palate (rare)

CARDIOVASCULAR:
[Heart];
Atrial septal defect;
Ventricular septal defect;
Vascular ring;
Mitral regurgitation, mild;
[Vascular]

GENITOURINARY:
[Kidneys];
Duplicated kidneys (rare)

SKELETAL:
[Spine];
Kyphosis;
S-scoliosis of thoracic spine;
[Limbs];
Flexion contractures at both knees;
[Hands];
Postaxial polydactyly

MUSCLE, SOFT TISSUE:
Muscle atrophy

NEUROLOGIC:
[Central nervous system];
Diffuse hypotonia;
Axial hypotonia;
Developmental delay;
Mental retardation, profound;
No language;
Asperger-like features;
Increased tendon reflex;
Seizures;
Megalencephaly;
Thick corpus callosum;
Mildly thin corpus callosum;
Enlarged white matter;
Focal pachygyria;
Polymicrogyria;
Wide Sylvian fissures with incomplete opercularization;
Ventricles slightly enlarged;
Hydrocephalus;
Cavum septi pellucidi;
Cavum vergae;
Small cavum septum

NEOPLASIA:
Increased risk of medulloblastoma (rare)

MOLECULAR BASIS:
Caused by mutation in the phosphatidylinositol 3-kinase, regulatory
subunit 2 gene (PIK3R2, 603157.0001);
Caused by mutation in the v-AKT murine thymoma viral oncogene homolog
3 gene (AKT3, 611223.0001)

*FIELD* CD
Nara Sobreira: 11/29/2012

*FIELD* ED
joanna: 11/30/2012
joanna: 11/29/2012

*FIELD* CN
Nara Sobreira - updated: 11/21/2012
Nara Sobreira - updated: 11/20/2012
Cassandra L. Kniffin - updated: 4/10/2012
Cassandra L. Kniffin - updated: 6/15/2011
Cassandra L. Kniffin - updated: 10/19/2009
Cassandra L. Kniffin - updated: 7/21/2008

*FIELD* CD
Victor A. McKusick: 12/29/1998

*FIELD* ED
carol: 11/21/2012
carol: 11/20/2012
alopez: 4/12/2012
ckniffin: 4/10/2012
carol: 6/20/2011
ckniffin: 6/15/2011
wwang: 11/6/2009
ckniffin: 10/19/2009
wwang: 8/4/2008
ckniffin: 7/21/2008
carol: 12/29/1998

MIM 611223
*RECORD*
*FIELD* NO
611223
*FIELD* TI
*611223 V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 3; AKT3
;;PROTEIN KINASE B, GAMMA; PKBG;;
read morePKB-GAMMA
MAGI3/AKT3 FUSION GENE, INCLUDED
*FIELD* TX

DESCRIPTION

Members of the AKT protein family, such as AKT3, are implicated in
numerous biologic processes, including adipocyte and muscle
differentiation, glycogen synthesis, glucose uptake, apoptosis, and
cellular proliferation (Nakatani et al., 1999).

CLONING

Using mouse Pkb-gamma to screen several human cDNA libraries, followed
by 5-prime RACE of a human brain cDNA library, Brodbeck et al. (1999)
cloned AKT3, which they called PKB-gamma. The deduced 479-amino acid
protein contains a pleckstrin (173570) homology (PH) domain, an
activation loop, and a C-terminal hydrophobic domain. PKB-gamma shares
83% and 78% amino acid identity with human PKB-alpha (AKT1; 164730) and
PKB-beta (AKT2; 164731), respectively, and more than 99% identity with
mouse Pkb-gamma. Northern blot analysis detected transcripts of 6.5 and
8.5 kb in all adult tissues examined, with highest expression in brain,
lung, and kidney and lowest expression in heart and liver. Transcripts
of the same size were detected in all fetal tissues examined except
kidney, with highest expression in heart, brain, and liver.

Independently, Nakatani et al. (1999) cloned AKT3. Northern blot
analysis detected highest expression of 5.3- and 7.7-kb transcripts in
brain, heart, and placenta, with weaker expression in skeletal muscle,
kidney, and pancreas.

GENE STRUCTURE

Nakatani et al. (1999) determined that the AKT3 gene contains 2 exons.

MAPPING

Using FISH, Murthy et al. (2000) mapped the AKT3 gene to chromosome
1q44. They mapped the mouse Akt3 gene to chromosome 1H4-H6.

CYTOGENETICS

Deletions of 1q42-q44 (612337) have been reported in a variety of
developmental abnormalities of brain, including microcephaly and
agenesis of the corpus callosum. Boland et al. (2007) described detailed
mapping studies of patients with unbalanced structural rearrangements of
distal 1q4. These defined a 3.5-Mb critical region that was hypothesized
to contain 1 or more genes that lead to agenesis of the corpus callosum
and microcephaly when present in only 1 functional copy. Mapping of a
balanced reciprocal t(1;13)(q44;q32) translocation in a patient with
postnatal microcephaly and agenesis of the corpus callosum demonstrated
a breakpoint in this region that was situated 20 kb upstream of AKT3, a
serine-threonine kinase. The murine ortholog Akt3 is required for
developmental regulation of normal brain size and callosal development.
Whereas sequencing of AKT3 in a panel of 45 patients with agenesis of
the corpus callosum did not demonstrate any pathogenic variations,
whole-mount in situ hybridization confirmed expression of AKT3 in the
developing central nervous system during mouse embryogenesis. Boland et
al. (2007) concluded that thus, AKT3 represents an excellent candidate
for developmental human microcephaly and agenesis of the corpus
callosum, and suggested that haploinsufficiency causes postnatal
microcephaly and agenesis of the corpus callosum.

GENE FUNCTION

Brodbeck et al. (1999) showed that PKB-gamma had low basal activity
following transfection into human embryonic kidney cells, but its
activity was stimulated 67-fold by pervanadate, an insulin (INS; 176730)
mimetic. Mutation of thr305 to ala in the activation loop of PKB-gamma
completely ablated its activation, whereas mutation of the C-terminal
regulatory site, ser472, reduced but did not abolish activation by
pervanadate. Activation of PKB-gamma by insulin required PI3K (see
PIK3CG; 601232) and was entirely due to phosphorylation at thr305.
Removal of the PH domain of PKB-gamma made phosphorylation of thr305
independent of PI3K activity.

Using Chinese hamster ovary cells expressing human insulin receptor
(INSR; 147670) and AKT3, Nakatani et al. (1999) showed that insulin
stimulated AKT3 activity and phosphorylation of AKT3 on thr305 and
ser472.

Poduri et al. (2012) compared the expression levels of the AKT1, AKT2,
and AKT3 genes by RNA-seq analysis of the perisylvian cortex of the
human brain at 9 weeks' gestation, during active neurogenesis, and found
that the AKT3 gene is expressed at higher levels than the AKT1 and AKT2
genes.

To assess the impact of AKT3, PIK3R2 (603157), and PIK3CA (171834)
mutations in individuals with megalencephaly on PI3K activity, Riviere
et al. (2012) used immunostaining to compare PIP3 amounts in
lymphoblastoid cell lines derived from 4 mutation carriers with
megalencephaly to those in control and PTEN-mutant cells. Consistent
with elevated PI3K activity, and similar to what is seen with PTEN
(601728) loss, all 3 lines with PIK3R2 or PIK3CA mutations showed
significantly more PIP3 staining than control cells, as well as greater
localization of active phosphoinositide-dependent kinase-1 (PDPK1;
605213) to the cell membrane. Treatment with the PI3K inhibitor PI-103
resulted in less PIP3 in the PIK3R2 G373R (603157.0001) and PIK3CA
glu453del (171834.0014) mutant lines, confirming that these results are
PI3K-dependent. Riviere et al. (2012) found no evidence for increased
PI3K activity in the AKT3-mutant line, consistent with a mutation
affecting a downstream effector of PI3K. Protein blot analysis showed
higher amounts of phosphorylated S6 protein and 4E-BP1 in all mutant
cell lines compared to controls. Although PI-103 treatment reduced S6
phosphorylation in control and mutant lines, the latter showed relative
resistance to PI3K inhibition, consistent with elevated signaling
through the pathway. Riviere et al. (2012) concluded that the
megalencephaly-associated mutations result in higher PI3K activity and
PI3K-mTOR signaling.

To determine whether individuals with hemimegalencephaly and a mutation
in PIK3CA (E545K; 171834.0003), AKT3 (E17K; 611223.0003), or MTOR
(C1483Y) have aberrant mTOR (601231) signaling, Lee et al. (2012)
immunostained brain sections of such cases with an antibody specific to
the phosphorylated epitope of the S6 protein in a standard assay for the
activation of mTOR signaling. Cells with the morphology of cytomegalic
neurons were strongly labeled for phosphorylated S6 in the
3-prime-diaminobenzidine (DAB) staining of HME brains. In addition, Lee
et al. (2012) coimmunostained for the neuronal marker MAP2, comparing
samples with age-matched, similarly processed non-HME cortical
hemisphere, and found a marked increase in the number of cells that were
positive for phosphorylated S6 and greater intensity of staining for
phosphorylated S6 in cytomegalic neurons of HME cases. Lee et al. (2012)
concluded that these mutations are associated with increased mTOR
signaling in affected brain regions.

MOLECULAR GENETICS

- Fusion Gene in Breast Cancer

Banerji et al. (2012) reported the whole-exome sequences of DNA from 103
human breast cancers of diverse subtypes from patients in Mexico and
Vietnam compared to matched-normal DNA, together with whole-genome
sequences of 22 breast cancer/normal pairs. They identified a recurrent
MAGI3/AKT3 fusion enriched in triple-negative breast cancers (TNBCs),
which lack estrogen receptors (133430), progesterone receptors (607311),
and ERBB2 (611223) expression. The MAGI3/AKT3 fusion leads to
constitutive activation of AKT kinase, which is abolished by treatment
with an ATP-competitive AKT small-molecule inhibitor.

- Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus
Syndrome

Riviere et al. (2012) performed exome sequencing in an individual with
clinical features overlapping both
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH;
603387) and megalencephaly-capillary malformation-polymicrogyria
syndrome (MCAP; 602501) and his parents and identified a de novo
mutation in the AKT3 gene (R465W; 611223.0001). Sanger sequencing of the
AKT3 gene in another 40 individuals with megalencephaly (many subjects
in this series had asymmetric brain enlargement, and several were
diagnosed with hemimegalencephaly) identified a different de novo
mutation in this gene in another individual with MPPH (N229S;
611223.0002). Riviere et al. (2012) suggested that the AKT3 gene is a
rare cause of megalencephaly (p = 0.002, calculated as the likelihood of
observing a second de novo mutation in the AKT3 gene).

In 8 samples of brain tissue from individuals with hemimegalencephaly
(HME), Poduri et al. (2012) identified somatic duplications of
chromosome 1q encompassing the AKT3 gene in 2. Sequencing of the AKT3
gene in the other 6 samples identified 1 with a known activating
mutation (E17K; 611223.0003); the mutation was not detectable in blood
from this patient.

Lee et al. (2012) performed whole-exome sequencing on brain and
peripheral blood DNA from 5 HME cases and identified 3 missense
mutations: one in the PIK3CA gene (E545K; 171834.0003), one in the AKT3
gene (E17K; 611223.0003), and one in the MTOR gene (C1483Y). The
individual with the MTOR gene mutation also carried a diagnosis of
hypomelanosis of Ito (300337). Lee et al. (2012) then used a modified
single base-extension protocol followed by mass spectrometry analysis to
detect somatic mutations at a frequency as low as 3% in genetically
heterogeneous samples. Reanalysis of the same DNA samples used for
whole-exome sequencing again showed the absence of the mutant allele in
blood but its presence in the brain, with similar mutation burden as
that detected with Illumina sequencing. These somatic mutations were
detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample.
Using the same technology, Lee et al. (2012) screened for these
mutations in 15 other HME cases and identified 3 additional cases
carrying the PIK3CA E545K variant, each with a mutation burden of about
30%. One of these individuals had hypertrophic regions in the right hand
and foot.

ANIMAL MODEL

Easton et al. (2005) found that Akt3-null mice had a selective 20%
decrease in brain size due to smaller and fewer cells. This was in
contrast to Akt1 (164730)-null mice, who showed a proportional decrease
in the size of all organs in addition to the brain. Mammalian target of
rapamycin (MTOR; 601231) signaling was attenuated in the brains of
Akt3-null mice, but not Akt1-null mice, suggesting that differential
regulation of this pathway contributes to an isoform-specific regulation
of cell growth. The findings showed the importance of insulin signaling
through PI3K and the Akt genes for the regulation of cell and organ
growth in mammals.

*FIELD* AV
.0001
MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME
AKT3, ARG465TRP

Riviere et al. (2012) performed exome sequencing in an individual with
clinical features overlapping
megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH;
603387) and megalencephaly-capillary malformation-polymicrogyria
syndrome (MCAP; 602501) and identified a de novo 1393C-T transition in
the AKT3 gene, resulting in an arg465-to-trp (R465W) substitution. The
mutation was not found in his parents. Also see 611223.0002. This
patient (LR08-018) had previously been reported by Mirzaa et al. (2012).

.0002
MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME
AKT3, ASN229SER

In 40 individuals with megalencephaly (many with asymmetric brain
enlargement, and several diagnosed with hemimegalencephaly), Riviere et
al. (2012) performed Sanger sequencing of the AKT3 gene and identified a
de novo 686A-G transition, resulting in an asn229-to-ser (N229S)
substitution, in 1 individual with MPPH (603387). Riviere et al. (2012)
suggested that the AKT3 gene is a rare cause of megalencephaly (p =
0.002, calculated as the likelihood of observing a second de novo
mutation in the AKT3 gene). See 611223.0001.

.0003
MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME,
SOMATIC
AKT3, GLU17LYS

Poduri et al. (2012) sequenced the AKT3 gene as a candidate gene in 8
samples of brain tissue from patients with hemimegalencephaly (HME; see
MPPH, 603387) and identified 1 with a 49G-A transition resulting in a
glu17-to-lys mutation (E17K) substitution. This mutation was not
detectable in DNA derived from the patient's leukocytes.

Lee et al. (2012) performed whole-exome sequencing on brain and
peripheral blood DNA from 5 patients with HME and identified the E17K
mutation in the AKT3 gene in 1. The mutant allele was absent in blood
but present in the brain, with a mutation burden of 40.4%.

*FIELD* RF
1. Banerji, S.; Cibulskis, K.; Rangel-Escareno, C.; Brown, K. K.;
Carter, S. L.; Frederick, A. M.; Lawrence, M. S.; Sivachenko, A. Y.;
Sougnez, C.; Zou, L.; Cortes, M. L.; Fernandez-Lopez, J. C.; and
35 others: Sequence analysis of mutations and translocations across
breast cancer subtypes. Nature 486: 405-409, 2012.

2. Boland, E.; Clayton-Smith, J.; Woo, V. G.; McKee, S.; Manson, F.
D. C.; Medne, L.; Zackai, E.; Swanson, E. A.; Fitzpatrick, D.; Millen,
K. J.; Sherr, E. H.; Dobyns, W. B.; Black, G. C. M.: Mapping of deletion
and translocation breakpoints in 1q44 implicates the serine/threonine
kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am.
J. Hum. Genet. 81: 292-303, 2007.

3. Brodbeck, D.; Cron, P.; Hemmings, B. A.: A human protein kinase
B-gamma with regulatory phosphorylation sites in the activation loop
and in the C-terminal hydrophobic domain. J. Biol. Chem. 274: 9133-9136,
1999.

4. Easton, R. M.; Cho, H.; Roovers, K.; Shineman, D. W.; Mizrahi,
M.; Forman, M. S.; Lee, V. M.-Y.; Szabolcs, M.; de Jong, R.; Oltersdorf,
T.; Ludwig, T.; Efstratiadis, A.; Birnbaum, M. J.: Role for Akt3/protein
kinase B-gamma in attainment of normal brain size. Molec. Cell Biol. 25:
1869-1878, 2005.

5. Lee, J. H.; Huynh, M.; Silhavy, J. L.; Kim, S.; Dixon-Salazar,
T.; Heiberg, A.; Scott, E.; Bafna, V.; Hill, K. J.; Collazo, A.; Funari,
V.; Russ, C.; Gabriel, S. B.; Mathern, G. W.; Gleeson, J. G.: De
novo somatic mutations in components of the PI3K-AKT3-mTOR pathway
cause hemimegalencephaly. Nature Genet. 44: 941-945, 2012.

6. Mirzaa, G. M.; Conway, R. L.; Gripp, K. W.; Lerman-Sagie, T.; Siegel,
D. H.; deVries, L. S.; Lev, D.; Kramer, N.; Hopkins, E.; Graham, J.
M., Jr.; Dobyns, W. B.: Megalencephaly-capillary malformation (MCAP)
and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH)
syndromes: two closely related disorders of brain overgrowth and abnormal
brain and body morphogenesis. Am. J. Med. Genet. 158A: 269-291,
2012.

7. Murthy, S. S.; Tosolini, A.; Taguchi, T.; Testa, J. R.: Mapping
of AKT3, encoding a member of the Akt/protein kinase B family, to
human and rodent chromosomes by fluorescence in situ hybridization. Cytogenet.
Cell Genet. 88: 38-40, 2000.

8. Nakatani, K.; Sakaue, H.; Thompson, D. A.; Weigel, R. J.; Roth,
R. A.: Identification of a human Akt3 (protein kinase B gamma) which
contains the regulatory serine phosphorylation site. Biochem. Biophys.
Res. Commun. 257: 906-910, 1999.

9. Poduri, A.; Evrony, G. D.; Cai, X.; Elhosary, P. C.; Beroukhim,
R.; Lehtinen, M. K.; Hills, L. B.; Heinzen, E. L.; Hill, A.; Hill,
R. S.; Barry, B. J.; Bourgeois, B. F. D.; Riviello, J. J.; Barkovich,
A. J.; Black, P. M.; Ligon, K. L.; Walsh, C. A.: Somatic activation
of AKT3 causes hemispheric developmental brain malformations. Neuron 74:
41-48, 2012.

10. Riviere, J.-B.; Mirzaa, G. M.; O'Roak, B. J.; Beddaoui, M.; Alcantara,
D.; Conway, R. L.; St-Onge, J.; Schwartzentruber, J. A.; Gripp, K.
W.; Nikkel, S. M.; Worthylake, T.; Sullivan, C. T.; and 29 others
: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA
cause a spectrum of related megalencephaly syndromes. Nature Genet. 44:
934-940, 2012.

*FIELD* CN
Nara Sobreira - updated: 11/21/2012
Ada Hamosh - updated: 7/20/2012
Cassandra L. Kniffin - updated: 4/17/2012
Victor A. McKusick - updated: 8/16/2007
Victor A. McKusick - updated: 7/26/2007

*FIELD* CD
Patricia A. Hartz: 7/18/2007

*FIELD* ED
carol: 06/04/2013
carol: 11/21/2012
alopez: 7/20/2012
terry: 5/2/2012
carol: 4/17/2012
ckniffin: 4/17/2012
wwang: 6/29/2011
alopez: 8/20/2007
terry: 8/16/2007
alopez: 7/30/2007
terry: 7/26/2007
mgross: 7/18/2007