TSC2_HUMAN
ID TSC2_HUMAN Reviewed; 1807 AA.
AC P49815; A7E2E2; B4DIL8; B4DIQ7; B4DRN2; B7Z2B8; C9J378; O75275; Q4LE71;
AC Q8TAZ1;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 2.
DT 03-AUG-2022, entry version 230.
DE RecName: Full=Tuberin;
DE AltName: Full=Tuberous sclerosis 2 protein;
GN Name=TSC2; Synonyms=TSC4;
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 VARIANT ARG-802.
RC TISSUE=Brain;
RX PubMed=8269512; DOI=10.1016/0092-8674(93)90618-z;
RG The European chromosome 16 tuberous sclerosis consortium;
RA Nellist M., Janssen B., Brook-Carter P.T., Hesseling-Janssen A.L.W.,
RA Maheshwar M.M., Verhoef S., van den Ouweland A.M.W., Lindhout D.,
RA Eussen B., Cordeiro I., Santos H., Halley D.J.J., Sampson J.R., Ward C.J.,
RA Peral B., Thomas S., Hughes J., Harris P.C., Roelfsema J.H., Saris J.J.,
RA Spruit L., Peters D.J.M., Dauwerse J.G., Breuning M.H.;
RT "Identification and characterization of the tuberous sclerosis gene on
RT chromosome 16.";
RL Cell 75:1305-1315(1993).
RN [2]
RP SEQUENCE REVISION.
RA Sampson J.R.;
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING (ISOFORMS 1; 2
RP AND 3).
RX PubMed=7558029; DOI=10.1006/geno.1995.1079;
RA Xu L., Sterner C., Maheshwar M.M., Wilson P.J., Nellist M., Short M.P.,
RA Haines J.L., Sampson J.R., Ramesh V.;
RT "Alternative splicing of the tuberous sclerosis 2 (TSC2) gene in human and
RT mouse tissues.";
RL Genomics 27:475-480(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-94; PHE-320; PHE-619
RP AND ARG-802.
RX PubMed=8789450; DOI=10.1093/hmg/5.1.131;
RA Maheshwar M.M., Sandford R., Nellist M., Cheadle J.P., Sgotto B.,
RA Vaudin M., Sampson J.R.;
RT "Comparative analysis and genomic structure of the tuberous sclerosis 2
RT (TSC2) gene in human and pufferfish.";
RL Hum. Mol. Genet. 5:131-137(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8).
RC TISSUE=Brain;
RX PubMed=24722188; DOI=10.1038/ncomms4650;
RA Corominas R., Yang X., Lin G.N., Kang S., Shen Y., Ghamsari L., Broly M.,
RA Rodriguez M., Tam S., Wanamaker S.A., Fan C., Yi S., Tasan M., Lemmens I.,
RA Kuang X., Zhao N., Malhotra D., Michaelson J.J., Vacic V., Calderwood M.A.,
RA Roth F.P., Tavernier J., Horvath S., Salehi-Ashtiani K., Korkin D.,
RA Sebat J., Hill D.E., Hao T., Vidal M., Iakoucheva L.M.;
RT "Protein interaction network of alternatively spliced isoforms from brain
RT links genetic risk factors for autism.";
RL Nat. Commun. 5:3650-3650(2014).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 5; 6; 7 AND 8).
RC TISSUE=Amygdala, and Hippocampus;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Aortic endothelium;
RA Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M., Ohara R.,
RA Okazaki N., Koga H., Nagase T., Ohara O.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
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 [9]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Lymph;
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 [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-199.
RC TISSUE=Placenta;
RX PubMed=9831664; DOI=10.1016/s0378-1119(98)00485-5;
RA Imai K., Sarker A.H., Akiyama K., Ikeda S., Yao M., Tsutsui K.,
RA Shohmori T., Seki S.;
RT "Genomic structure and sequence of a human homologue (NTHL1/NTH1) of
RT Escherichia coli endonuclease III with those of the adjacent parts of TSC2
RT and SLC9A3R2 genes.";
RL Gene 222:287-295(1998).
RN [12]
RP INTERACTION WITH RABEP1.
RX PubMed=9045618; DOI=10.1074/jbc.272.10.6097;
RA Xiao G.-H., Shoarinejad F., Jin F., Golemis E.A., Yeung R.S.;
RT "The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase
RT activating protein (GAP) in modulating endocytosis.";
RL J. Biol. Chem. 272:6097-6100(1997).
RN [13]
RP INTERACTION WITH TSC1.
RX PubMed=9580671; DOI=10.1093/hmg/7.6.1053;
RA van Slegtenhorst M.A., Nellist M., Nagelkerken B., Cheadle J.P.,
RA Snell R.G., van den Ouweland A.M.W., Reuser A., Sampson J.R.,
RA Halley D.J.J., van der Sluijs P.;
RT "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene
RT products.";
RL Hum. Mol. Genet. 7:1053-1057(1998).
RN [14]
RP INTERACTION WITH TSC1.
RX PubMed=10585443; DOI=10.1074/jbc.274.50.35647;
RA Nellist M., van Slegtenhorst M.A., Goedbloed M., van den Ouweland A.M.W.,
RA Halley D.J.J., van der Sluijs P.;
RT "Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a
RT cytosolic chaperone for hamartin.";
RL J. Biol. Chem. 274:35647-35652(1999).
RN [15]
RP INVOLVEMENT IN LAM.
RX PubMed=11829138; DOI=10.1007/s10038-002-8651-8;
RA Sato T., Seyama K., Fujii H., Maruyama H., Setoguchi Y., Iwakami S.,
RA Fukuchi Y., Hino O.;
RT "Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with
RT pulmonary lymphangioleiomyomatosis.";
RL J. Hum. Genet. 47:20-28(2002).
RN [16]
RP PHOSPHORYLATION AT SER-939 AND THR-1462.
RX PubMed=12150915; DOI=10.1016/s1097-2765(02)00568-3;
RA Manning B.D., Tee A.R., Logsdon M.N., Blenis J., Cantley L.C.;
RT "Identification of the tuberous sclerosis complex-2 tumor suppressor gene
RT product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.";
RL Mol. Cell 10:151-162(2002).
RN [17]
RP FUNCTION, AND CHARACTERIZATION OF VARIANTS TSC2 MET-599 AND SER-1651.
RX PubMed=12271141; DOI=10.1073/pnas.202476899;
RA Tee A.R., Fingar D.C., Manning B.D., Kwiatkowski D.J., Cantley L.C.,
RA Blenis J.;
RT "Tuberous sclerosis complex-1 and -2 gene products function together to
RT inhibit mammalian target of rapamycin (mTOR)-mediated downstream
RT signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:13571-13576(2002).
RN [18]
RP PHOSPHORYLATION AT THR-1271 AND SER-1387, AND MUTAGENESIS OF THR-1271 AND
RP SER-1387.
RX PubMed=14651849; DOI=10.1016/s0092-8674(03)00929-2;
RA Inoki K., Zhu T., Guan K.L.;
RT "TSC2 mediates cellular energy response to control cell growth and
RT survival.";
RL Cell 115:577-590(2003).
RN [19]
RP FUNCTION, MUTAGENESIS OF 1637-LYS--ARG-1639; ARG-1745 AND
RP 1749-ARG--ARG-1751, AND CHARACTERIZATION OF VARIANTS TSC2 LYS-1643;
RP SER-1651; LYS-1681 AND PRO-1743.
RX PubMed=15340059; DOI=10.1128/mcb.24.18.7965-7975.2004;
RA Li Y., Inoki K., Guan K.-L.;
RT "Biochemical and functional characterizations of small GTPase Rheb and TSC2
RT GAP activity.";
RL Mol. Cell. Biol. 24:7965-7975(2004).
RN [20]
RP PHOSPHORYLATION AT SER-1798.
RX PubMed=15342917; DOI=10.1073/pnas.0405659101;
RA Roux P.P., Ballif B.A., Anjum R., Gygi S.P., Blenis J.;
RT "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous
RT sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:13489-13494(2004).
RN [21]
RP PHOSPHORYLATION AT SER-1387; SER-1418 AND SER-1420, IDENTIFICATION BY MASS
RP SPECTROMETRY, INTERACTION WITH HSPA1; HSPA8 AND TSC1, AND CHARACTERIZATION
RP OF VARIANTS TSC2 TRP-611 AND GLN-611.
RX PubMed=15963462; DOI=10.1016/j.bbrc.2005.05.175;
RA Nellist M., Burgers P.C., van den Ouweland A.M.W., Halley D.J.J.,
RA Luider T.M.;
RT "Phosphorylation and binding partner analysis of the TSC1-TSC2 complex.";
RL Biochem. Biophys. Res. Commun. 333:818-826(2005).
RN [22]
RP INTERACTION WITH HERC1 AND TSC1.
RX PubMed=16464865; DOI=10.1074/jbc.c500451200;
RA Chong-Kopera H., Inoki K., Li Y., Zhu T., Garcia-Gonzalo F.R., Rosa J.L.,
RA Guan K.-L.;
RT "TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the
RT HERC1 ubiquitin ligase.";
RL J. Biol. Chem. 281:8313-8316(2006).
RN [23]
RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL38.
RX PubMed=18407068; DOI=10.1016/j.chom.2008.03.002;
RA Moorman N.J., Cristea I.M., Terhune S.S., Rout M.P., Chait B.T., Shenk T.;
RT "Human cytomegalovirus protein UL38 inhibits host cell stress responses by
RT antagonizing the tuberous sclerosis protein complex.";
RL Cell Host Microbe 3:253-262(2008).
RN [24]
RP UBIQUITINATION BY MYCBP2, PHOSPHORYLATION AT SER-540; SER-664; SER-939;
RP THR-1462 AND SER-1798, AND CHARACTERIZATION OF VARIANT GLN-611.
RX PubMed=18308511; DOI=10.1016/j.cellsig.2008.01.020;
RA Han S., Witt R.M., Santos T.M., Polizzano C., Sabatini B.L., Ramesh V.;
RT "Pam (Protein associated with Myc) functions as an E3 ubiquitin ligase and
RT regulates TSC/mTOR signaling.";
RL Cell. Signal. 20:1084-1091(2008).
RN [25]
RP UBIQUITINATION, AND INTERACTION WITH FBXW5.
RX PubMed=18381890; DOI=10.1101/gad.1624008;
RA Hu J., Zacharek S., He Y.J., Lee H., Shumway S., Duronio R.J., Xiong Y.;
RT "WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by
RT DDB1-CUL4-ROC1 ligase.";
RL Genes Dev. 22:866-871(2008).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-927; SER-981; SER-1132;
RP SER-1155; SER-1337; SER-1338; SER-1387; SER-1411; SER-1420 AND SER-1452,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [30]
RP PHOSPHORYLATION BY DAPK1, AND INTERACTION WITH DAPK1.
RX PubMed=18974095; DOI=10.1074/jbc.m805165200;
RA Stevens C., Lin Y., Harrison B., Burch L., Ridgway R.A., Sansom O.,
RA Hupp T.;
RT "Peptide combinatorial libraries identify TSC2 as a death-associated
RT protein kinase (DAPK) death domain-binding protein and reveal a stimulatory
RT role for DAPK in mTORC1 signaling.";
RL J. Biol. Chem. 284:334-344(2009).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1155; THR-1462 AND SER-1798,
RP AND 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 [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1346 AND SER-1798, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [33]
RP INTERACTION WITH NAA10.
RX PubMed=20145209; DOI=10.1126/scisignal.2000590;
RA Kuo H.P., Lee D.F., Chen C.T., Liu M., Chou C.K., Lee H.J., Du Y., Xie X.,
RA Wei Y., Xia W., Weihua Z., Yang J.Y., Yen C.J., Huang T.H., Tan M.,
RA Xing G., Zhao Y., Lin C.H., Tsai S.F., Fidler I.J., Hung M.C.;
RT "ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR
RT signaling pathway.";
RL Sci. Signal. 3:RA9-RA9(2010).
RN [34]
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., Buerckstuemmer T.,
RA 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 [35]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1132, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-981; SER-1346; SER-1364;
RP SER-1411; SER-1420; SER-1452 AND SER-1799, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1411, AND IDENTIFICATION BY
RP 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 [38]
RP INTERACTION WITH RRAGA.
RX PubMed=25936802; DOI=10.1016/j.molcel.2015.03.033;
RA Deng L., Jiang C., Chen L., Jin J., Wei J., Zhao L., Chen M., Pan W.,
RA Xu Y., Chu H., Wang X., Ge X., Li D., Liao L., Liu M., Li L., Wang P.;
RT "The ubiquitination of RagA GTPase by RNF152 negatively regulates mTORC1
RT activation.";
RL Mol. Cell 58:804-818(2015).
RN [39]
RP UBIQUITINATION.
RX PubMed=27278822; DOI=10.1038/ncomms11803;
RA Bento C.F., Ashkenazi A., Jimenez-Sanchez M., Rubinsztein D.C.;
RT "The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate
RT autophagy via a common pathway.";
RL Nat. Commun. 7:11803-11803(2016).
RN [40]
RP FUNCTION, INTERACTION WITH TSC1, INVOLVEMENT IN FCORD2, VARIANT FCORD2
RP ILE-1547, AND CHARACTERIZATION OF VARIANT FCORD2 ILE-1547.
RX PubMed=28215400; DOI=10.1016/j.ajhg.2017.01.030;
RA Lim J.S., Gopalappa R., Kim S.H., Ramakrishna S., Lee M., Kim W.I., Kim J.,
RA Park S.M., Lee J., Oh J.H., Kim H.D., Park C.H., Lee J.S., Kim S.,
RA Kim D.S., Han J.M., Kang H.C., Kim H.H., Lee J.H.;
RT "Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia.";
RL Am. J. Hum. Genet. 100:454-472(2017).
RN [41]
RP IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; STIP1; CDC37; PPP5C; PTGES3;
RP TSC1; AKT; CDK4; RAF1 AND NR3C1, AND INTERACTION WITH HSP90AA1 AND TSC1.
RX PubMed=29127155; DOI=10.15252/embj.201796700;
RA Woodford M.R., Sager R.A., Marris E., Dunn D.M., Blanden A.R., Murphy R.L.,
RA Rensing N., Shapiro O., Panaretou B., Prodromou C., Loh S.N., Gutmann D.H.,
RA Bourboulia D., Bratslavsky G., Wong M., Mollapour M.;
RT "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding
RT of kinase and non-kinase clients.";
RL EMBO J. 36:3650-3665(2017).
RN [42]
RP INTERACTION WITH RPAP3 AND URI1.
RX PubMed=28561026; DOI=10.1038/ncomms15615;
RA Cloutier P., Poitras C., Durand M., Hekmat O., Fiola-Masson E.,
RA Bouchard A., Faubert D., Chabot B., Coulombe B.;
RT "R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2
RT to regulate assembly of U5 small nuclear ribonucleoprotein.";
RL Nat. Commun. 8:15615-15615(2017).
RN [43]
RP INTERACTION WITH WDR45B.
RX PubMed=28561066; DOI=10.1038/ncomms15637;
RA Bakula D., Mueller A.J., Zuleger T., Takacs Z., Franz-Wachtel M.,
RA Thost A.K., Brigger D., Tschan M.P., Frickey T., Robenek H., Macek B.,
RA Proikas-Cezanne T.;
RT "WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling
RT circuits in the control of autophagy.";
RL Nat. Commun. 8:15637-15637(2017).
RN [44]
RP INTERACTION WITH YWHAG.
RX PubMed=33473107; DOI=10.1038/s41467-020-20780-2;
RA Wang W., Li J., Tan J., Wang M., Yang J., Zhang Z.M., Li C.,
RA Basnakian A.G., Tang H.W., Perrimon N., Zhou Q.;
RT "Endonuclease G promotes autophagy by suppressing mTOR signaling and
RT activating the DNA damage response.";
RL Nat. Commun. 12:476-476(2021).
RN [45]
RP VARIANTS TSC2 ILE-449; TRP-611; LEU-1227; TRP-1240; PHE-1509 DEL AND
RP GLU-1712.
RX PubMed=8824881; DOI=10.1093/hmg/5.2.249;
RA Wilson P.J., Ramesh V., Kristiansen A., Bove C., Jozwiak S.,
RA Kwiatkowski D.J., Short M.P., Haines J.L.;
RT "Novel mutations detected in the TSC2 gene from both sporadic and familial
RT TSC patients.";
RL Hum. Mol. Genet. 5:249-256(1996).
RN [46]
RP VARIANTS TSC2 PHE-1509 DEL; MET-1594; LYS-1643; SER-1651; LEU-1675 AND
RP LYS-1681.
RX PubMed=9302281; DOI=10.1093/hmg/6.11.1991;
RA Maheshwar M.M., Cheadle J.P., Jones A.C., Myring J., Fryer A.E.,
RA Harris P.C., Sampson J.R.;
RT "The GAP-related domain of tuberin, the product of the TSC2 gene, is a
RT target for missense mutations in tuberous sclerosis.";
RL Hum. Mol. Genet. 6:1991-1996(1997).
RN [47]
RP VARIANTS TSC2.
RX PubMed=9463313; DOI=10.1086/301705;
RA Au K.-S., Rodriguez J.A., Finch J.L., Volcik K.A., Roach E.S.,
RA Delgado M.R., Rodriguez E. Jr., Northrup H.;
RT "Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis
RT patients.";
RL Am. J. Hum. Genet. 62:286-294(1998).
RN [48]
RP VARIANTS TSC2.
RX PubMed=9829910;
RX DOI=10.1002/(sici)1098-1004(1998)12:6<408::aid-humu7>3.0.co;2-p;
RA Beauchamp R.L., Banwell A., McNamara P., Jacobsen M., Higgins E.,
RA Northrup H., Short M.P., Sims K., Ozelius L., Ramesh V.;
RT "Exon scanning of the entire TSC2 gene for germline mutations in 40
RT unrelated patients with tuberous sclerosis.";
RL Hum. Mutat. 12:408-416(1998).
RN [49]
RP VARIANTS TSC2.
RX PubMed=10732801; DOI=10.1007/s100480050039;
RA Gilbert J.R., Guy V., Kumar A., Wolpert C., Kandt R., Aylesworth A.,
RA Roses A.D., Pericak-Vance M.A.;
RT "Mutation and polymorphism analysis in the tuberous sclerosis 2 (TSC2)
RT gene.";
RL Neurogenetics 1:267-272(1998).
RN [50]
RP VARIANTS TSC2, AND VARIANTS.
RX PubMed=10205261; DOI=10.1086/302381;
RA Jones A.C., Shyamsundar M.M., Thomas M.W., Maynard J., Idziaszczyk S.A.,
RA Tomkins S., Sampson J.R., Cheadle J.P.;
RT "Comprehensive mutation analysis of TSC1 and TSC2- and phenotypic
RT correlations in 150 families with tuberous sclerosis.";
RL Am. J. Hum. Genet. 64:1305-1315(1999).
RN [51]
RP VARIANT TSC2 ARG-717.
RX PubMed=10069705;
RX DOI=10.1002/(sici)1096-8628(19990219)82:5<368::aid-ajmg2>3.0.co;2-i;
RA Zhang H., Yamamoto T., Nanba E., Kitamura Y., Terada T., Akaboshi S.,
RA Yuasa I., Ohtani K., Nakamoto S., Takeshita K., Ohno K.;
RT "Novel TSC2 mutation in a patient with pulmonary tuberous sclerosis: lack
RT of loss of heterozygosity in a lung cyst.";
RL Am. J. Med. Genet. 82:368-370(1999).
RN [52]
RP VARIANTS TSC2, AND VARIANTS.
RX PubMed=10735580; DOI=10.1046/j.1469-1809.1999.6350383.x;
RA Choy Y.S., Dabora S.L., Hall F., Ramesh V., Niida Y., Franz D.,
RA Kasprzyk-Obara J., Reeve M.P., Kwiatkowski D.J.;
RT "Superiority of denaturing high performance liquid chromatography over
RT single-stranded conformation and conformation-sensitive gel electrophoresis
RT for mutation detection in TSC2.";
RL Ann. Hum. Genet. 63:383-391(1999).
RN [53]
RP VARIANTS TSC2, AND VARIANTS.
RC TISSUE=Blood, and Lymphoblast;
RX PubMed=10533067;
RX DOI=10.1002/(sici)1098-1004(199911)14:5<412::aid-humu7>3.0.co;2-k;
RA Niida Y., Lawrence-Smith N., Banwell A., Hammer E., Lewis J.,
RA Beauchamp R.L., Sims K., Ramesh V., Ozelius L.;
RT "Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated
RT patients with tuberous sclerosis.";
RL Hum. Mutat. 14:412-422(1999).
RN [54]
RP VARIANTS TSC2 ARG-137; GLN-611; ASN-647; ARG-717; GLU-769; MET-963 AND
RP LEU-1675, VARIANT PHE-320, AND POSSIBLE ASSOCIATION WITH TSC.
RX PubMed=10570911; DOI=10.1007/s100380050185;
RA Zhang H., Nanba E., Yamamoto T., Ninomiya H., Ohno K., Mizuguchi M.,
RA Takeshita K.;
RT "Mutational analysis of TSC1 and TSC2 genes in Japanese patients with
RT tuberous sclerosis complex.";
RL J. Hum. Genet. 44:391-396(1999).
RN [55]
RP VARIANTS TSC2 TRP-611; TRP-905; PRO-1744 AND 1746-HIS--ARG-1751 DEL, AND
RP VARIANT PHE-320.
RC TISSUE=Peripheral blood leukocyte;
RX PubMed=10607950;
RX DOI=10.1002/(sici)1096-8628(20000117)90:2<123::aid-ajmg7>3.0.co;2-l;
RA Yamashita Y., Ono J., Okada S., Wataya-Kaneda M., Yoshikawa K.,
RA Nishizawa M., Hirayama Y., Kobayashi E., Seyama K., Hino O.;
RT "Analysis of all exons of TSC1 and TSC2 genes for germline mutations in
RT Japanese patients with tuberous sclerosis: report of 10 mutations.";
RL Am. J. Med. Genet. 90:123-126(2000).
RN [56]
RP VARIANT LAM GLN-611.
RX PubMed=10823953; DOI=10.1073/pnas.97.11.6085;
RA Carsillo T., Astrinidis A., Henske E.P.;
RT "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of
RT sporadic pulmonary lymphangioleiomyomatosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:6085-6090(2000).
RN [57]
RP VARIANTS TSC2 SER-1651; PHE-1653; LEU-1675 AND 1746-HIS--ARG-1751 DEL, AND
RP VARIANTS THR-607; VAL-862; SER-1429 AND ARG-1450.
RX PubMed=15024740; DOI=10.1002/humu.9225;
RA Feng J.-H., Yamamoto T., Nanba E., Ninomiya H., Oka A., Ohno K.;
RT "Novel TSC2 mutations and decreased expression of tuberin in cultured tumor
RT cells with an insertion mutation.";
RL Hum. Mutat. 23:397-397(2004).
RN [58]
RP VARIANTS TSC2 GLN-611; TRP-611 AND PRO-1027, AND VARIANTS GLN-367;
RP ARG-1341; ASN-1636 AND LEU-1673.
RX PubMed=15595939; DOI=10.1111/j.1600-0404.2004.00366.x;
RA Ali M., Girimaji S.C., Markandaya M., Shukla A.K., Sacchidanand S.,
RA Kumar A.;
RT "Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian
RT patients with tuberous sclerosis complex.";
RL Acta Neurol. Scand. 111:54-63(2005).
CC -!- FUNCTION: In complex with TSC1, this tumor suppressor inhibits the
CC nutrient-mediated or growth factor-stimulated phosphorylation of S6K1
CC and EIF4EBP1 by negatively regulating mTORC1 signaling
CC (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein
CC (GAP) for the small GTPase RHEB, a direct activator of the protein
CC kinase activity of mTORC1 (PubMed:15340059). May also play a role in
CC microtubule-mediated protein transport (By similarity). Also stimulates
CC the intrinsic GTPase activity of the Ras-related proteins RAP1A and
CC RAB5 (By similarity). {ECO:0000250|UniProtKB:P49816,
CC ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059,
CC ECO:0000269|PubMed:28215400}.
CC -!- SUBUNIT: Probably forms a complex composed of chaperones HSP90 and
CC HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and
CC client protein TSC2 (PubMed:29127155). Probably forms a complex
CC composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C,
CC TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex
CC does not contain co-chaperones STIP1/HOP and PTGES3/p23
CC (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2;
CC TSC1 is required to recruit TCS2 to the complex thereby stabilizing
CC TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction
CC with TSC1 stabilizes TSC2 and prevents the interaction with HERC1
CC (PubMed:9580671, PubMed:10585443, PubMed:15963462, PubMed:16464865).
CC May also interact with the adapter molecule RABEP1 (PubMed:9045618).
CC The final complex may contain TSC2 and RABEP1 linked to RAB5
CC (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462).
CC Interacts with DAPK1 (PubMed:18974095). Interacts with FBXW5
CC (PubMed:18381890). Interacts with NAA10 (via C-terminal domain)
CC (PubMed:20145209). Interacts with RRAGA (polyubiquitinated)
CC (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts
CC with RPAP3 and URI1 (PubMed:28561026). Interacts with YWHAG
CC (PubMed:33473107). {ECO:0000269|PubMed:10585443,
CC ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:16464865,
CC ECO:0000269|PubMed:18381890, ECO:0000269|PubMed:18974095,
CC ECO:0000269|PubMed:20145209, ECO:0000269|PubMed:25936802,
CC ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:28561026,
CC ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:29127155,
CC ECO:0000269|PubMed:33473107, ECO:0000269|PubMed:9045618,
CC ECO:0000269|PubMed:9580671}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus
CC protein UL38; this interaction inhibits cellular stress response
CC mediated by mTORC1. {ECO:0000269|PubMed:18407068}.
CC -!- INTERACTION:
CC P49815; Q9NRD5: PICK1; NbExp=2; IntAct=EBI-396587, EBI-79165;
CC P49815; P62136: PPP1CA; NbExp=2; IntAct=EBI-396587, EBI-357253;
CC P49815; O00141: SGK1; NbExp=4; IntAct=EBI-396587, EBI-1042854;
CC P49815; Q96EB6: SIRT1; NbExp=2; IntAct=EBI-396587, EBI-1802965;
CC P49815; Q92574: TSC1; NbExp=11; IntAct=EBI-396587, EBI-1047085;
CC P49815; P31946: YWHAB; NbExp=4; IntAct=EBI-396587, EBI-359815;
CC P49815; P63104: YWHAZ; NbExp=7; IntAct=EBI-396587, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane protein.
CC Note=At steady state found in association with membranes.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1;
CC IsoId=P49815-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49815-2; Sequence=VSP_004470;
CC Name=3;
CC IsoId=P49815-3; Sequence=VSP_004471;
CC Name=4;
CC IsoId=P49815-4; Sequence=VSP_004472;
CC Name=5;
CC IsoId=P49815-5; Sequence=VSP_004471, VSP_004472;
CC Name=6;
CC IsoId=P49815-6; Sequence=VSP_038355, VSP_004470, VSP_004472;
CC Name=7;
CC IsoId=P49815-7; Sequence=VSP_054163, VSP_004470, VSP_004472;
CC Name=8; Synonyms=H, I;
CC IsoId=P49815-8; Sequence=VSP_055896, VSP_055897;
CC -!- TISSUE SPECIFICITY: Liver, brain, heart, lymphocytes, fibroblasts,
CC biliary epithelium, pancreas, skeletal muscle, kidney, lung and
CC placenta.
CC -!- PTM: Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect
CC interaction with TSC1. Phosphorylation at Ser-939 and Thr-1462 by
CC PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by
CC AMPK activates it and leads to negative regulation of the mTORC1
CC complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation
CC inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by
CC DAPK1. {ECO:0000269|PubMed:12150915, ECO:0000269|PubMed:15342917,
CC ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:18308511}.
CC -!- PTM: Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase
CC complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2
CC independently of its phosphorylation status leading to subsequent
CC degradation; association with TSC1 protects from ubiquitination.
CC {ECO:0000269|PubMed:18308511, ECO:0000269|PubMed:18381890,
CC ECO:0000269|PubMed:27278822}.
CC -!- DISEASE: Tuberous sclerosis 2 (TSC2) [MIM:613254]: An autosomal
CC dominant multi-system disorder that affects especially the brain,
CC kidneys, heart, and skin. It is characterized by hamartomas (benign
CC overgrowths predominantly of a cell or tissue type that occurs normally
CC in the organ) and hamartias (developmental abnormalities of tissue
CC combination). Clinical manifestations include epilepsy, learning
CC difficulties, behavioral problems, and skin lesions. Seizures can be
CC intractable and premature death can occur from a variety of disease-
CC associated causes. {ECO:0000269|PubMed:10069705,
CC ECO:0000269|PubMed:10205261, ECO:0000269|PubMed:10533067,
CC ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950,
CC ECO:0000269|PubMed:10732801, ECO:0000269|PubMed:10735580,
CC ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15024740,
CC ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:15595939,
CC ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:8824881,
CC ECO:0000269|PubMed:9302281, ECO:0000269|PubMed:9463313,
CC ECO:0000269|PubMed:9829910}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and
CC often fatal lung disease characterized by a diffuse proliferation of
CC abnormal smooth muscle cells in the lungs. It affects almost
CC exclusively young women and can occur as an isolated disorder or in
CC association with tuberous sclerosis complex.
CC {ECO:0000269|PubMed:10823953, ECO:0000269|PubMed:11829138}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: A form of
CC focal cortical dysplasia, a malformation of cortical development that
CC results in medically refractory epilepsy in the pediatric population
CC and in adults. FCORD2 is a severe form, with onset usually in
CC childhood, characterized by disrupted cortical lamination and specific
CC cytological abnormalities. It is classified in 2 subtypes: type IIA
CC characterized by dysmorphic neurons and lack of balloon cells; type IIB
CC with dysmorphic neurons and balloon cells.
CC {ECO:0000269|PubMed:28215400}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 8]: May be due to an intron retention.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAE06082.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TSC2ID184.html";
CC -!- WEB RESOURCE: Name=Tuberous sclerosis database Tuberous sclerosis 2
CC (TSC2); Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/TSC2";
CC ---------------------------------------------------------------------------
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DR EMBL; X75621; CAA53287.1; -; mRNA.
DR EMBL; L48546; AAB41564.1; -; Genomic_DNA.
DR EMBL; L48517; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48518; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48519; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48521; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48522; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48523; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48524; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48525; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48526; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48527; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48528; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48529; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48530; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48531; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48532; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48533; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48534; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48535; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48536; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48537; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48538; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48539; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48540; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48541; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48542; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48543; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48544; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; L48545; AAB41564.1; JOINED; Genomic_DNA.
DR EMBL; KJ535038; AHW56677.1; -; mRNA.
DR EMBL; KJ535051; AHW56690.1; -; mRNA.
DR EMBL; AK294548; BAH11804.1; -; mRNA.
DR EMBL; AK295672; BAG58530.1; -; mRNA.
DR EMBL; AK295728; BAG58569.1; -; mRNA.
DR EMBL; AK299343; BAG61344.1; -; mRNA.
DR EMBL; AB210000; BAE06082.1; ALT_INIT; mRNA.
DR EMBL; AC005600; AAC34210.1; -; Genomic_DNA.
DR EMBL; AC093513; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471112; EAW85556.1; -; Genomic_DNA.
DR EMBL; BC150300; AAI50301.1; -; mRNA.
DR EMBL; BC025364; AAH25364.1; -; mRNA.
DR EMBL; BC046929; AAH46929.1; -; mRNA.
DR EMBL; AB014460; BAA32694.1; -; Genomic_DNA.
DR CCDS; CCDS10458.1; -. [P49815-1]
DR CCDS; CCDS10459.1; -. [P49815-2]
DR CCDS; CCDS45384.1; -. [P49815-4]
DR CCDS; CCDS58408.1; -. [P49815-5]
DR CCDS; CCDS81933.1; -. [P49815-6]
DR CCDS; CCDS81934.1; -. [P49815-7]
DR PIR; A49420; A49420.
DR RefSeq; NP_000539.2; NM_000548.4. [P49815-1]
DR RefSeq; NP_001070651.1; NM_001077183.2. [P49815-5]
DR RefSeq; NP_001107854.1; NM_001114382.2. [P49815-4]
DR RefSeq; NP_001305756.1; NM_001318827.1. [P49815-6]
DR RefSeq; NP_001305758.1; NM_001318829.1. [P49815-7]
DR RefSeq; NP_001305760.1; NM_001318831.1.
DR RefSeq; NP_001305761.1; NM_001318832.1.
DR RefSeq; XP_005255586.2; XM_005255529.4.
DR RefSeq; XP_016879105.1; XM_017023616.1.
DR PDB; 7DL2; EM; 4.40 A; A/B=50-1807.
DR PDBsum; 7DL2; -.
DR AlphaFoldDB; P49815; -.
DR SMR; P49815; -.
DR BioGRID; 113100; 173.
DR ComplexPortal; CPX-6142; TSC1-TSC2 complex.
DR CORUM; P49815; -.
DR IntAct; P49815; 52.
DR MINT; P49815; -.
DR STRING; 9606.ENSP00000219476; -.
DR iPTMnet; P49815; -.
DR PhosphoSitePlus; P49815; -.
DR SwissPalm; P49815; -.
DR BioMuta; TSC2; -.
DR DMDM; 269849475; -.
DR EPD; P49815; -.
DR jPOST; P49815; -.
DR MassIVE; P49815; -.
DR MaxQB; P49815; -.
DR PaxDb; P49815; -.
DR PeptideAtlas; P49815; -.
DR PRIDE; P49815; -.
DR ProteomicsDB; 4311; -.
DR ProteomicsDB; 56142; -. [P49815-1]
DR ProteomicsDB; 56143; -. [P49815-2]
DR ProteomicsDB; 56144; -. [P49815-3]
DR ProteomicsDB; 56145; -. [P49815-4]
DR ProteomicsDB; 56146; -. [P49815-5]
DR ProteomicsDB; 56147; -. [P49815-6]
DR ABCD; P49815; 1 sequenced antibody.
DR Antibodypedia; 3702; 2076 antibodies from 45 providers.
DR DNASU; 7249; -.
DR Ensembl; ENST00000219476.9; ENSP00000219476.3; ENSG00000103197.18. [P49815-1]
DR Ensembl; ENST00000350773.9; ENSP00000344383.4; ENSG00000103197.18. [P49815-4]
DR Ensembl; ENST00000382538.10; ENSP00000371978.6; ENSG00000103197.18. [P49815-7]
DR Ensembl; ENST00000401874.7; ENSP00000384468.2; ENSG00000103197.18. [P49815-5]
DR Ensembl; ENST00000439673.6; ENSP00000399232.2; ENSG00000103197.18. [P49815-6]
DR Ensembl; ENST00000642936.1; ENSP00000494514.1; ENSG00000103197.18. [P49815-3]
DR Ensembl; ENST00000644043.1; ENSP00000496262.1; ENSG00000103197.18. [P49815-2]
DR GeneID; 7249; -.
DR KEGG; hsa:7249; -.
DR MANE-Select; ENST00000219476.9; ENSP00000219476.3; NM_000548.5; NP_000539.2.
DR UCSC; uc002con.4; human. [P49815-1]
DR CTD; 7249; -.
DR DisGeNET; 7249; -.
DR GeneCards; TSC2; -.
DR GeneReviews; TSC2; -.
DR HGNC; HGNC:12363; TSC2.
DR HPA; ENSG00000103197; Low tissue specificity.
DR MalaCards; TSC2; -.
DR MIM; 191092; gene.
DR MIM; 606690; phenotype.
DR MIM; 607341; phenotype.
DR MIM; 613254; phenotype.
DR neXtProt; NX_P49815; -.
DR OpenTargets; ENSG00000103197; -.
DR Orphanet; 210159; Adult hepatocellular carcinoma.
DR Orphanet; 88924; Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis.
DR Orphanet; 269001; Isolated focal cortical dysplasia type IIa.
DR Orphanet; 269008; Isolated focal cortical dysplasia type IIb.
DR Orphanet; 538; Lymphangioleiomyomatosis.
DR Orphanet; 805; Tuberous sclerosis complex.
DR PharmGKB; PA37035; -.
DR VEuPathDB; HostDB:ENSG00000103197; -.
DR eggNOG; KOG3687; Eukaryota.
DR GeneTree; ENSGT00950000183139; -.
DR HOGENOM; CLU_001122_0_0_1; -.
DR InParanoid; P49815; -.
DR OMA; CDIMSAI; -.
DR OrthoDB; 341431at2759; -.
DR PhylomeDB; P49815; -.
DR TreeFam; TF324484; -.
DR PathwayCommons; P49815; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR Reactome; R-HSA-165181; Inhibition of TSC complex formation by PKB.
DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-HSA-380972; Energy dependent regulation of mTOR by LKB1-AMPK.
DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-8854214; TBC/RABGAPs.
DR SABIO-RK; P49815; -.
DR SignaLink; P49815; -.
DR SIGNOR; P49815; -.
DR BioGRID-ORCS; 7249; 142 hits in 1104 CRISPR screens.
DR ChiTaRS; TSC2; human.
DR GeneWiki; TSC2; -.
DR GenomeRNAi; 7249; -.
DR Pharos; P49815; Tbio.
DR PRO; PR:P49815; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P49815; protein.
DR Bgee; ENSG00000103197; Expressed in right hemisphere of cerebellum and 185 other tissues.
DR ExpressionAtlas; P49815; baseline and differential.
DR Genevisible; P49815; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; IDA:SynGO.
DR GO; GO:0033596; C:TSC1-TSC2 complex; IDA:UniProtKB.
DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; IPI:UniProtKB.
DR GO; GO:0019902; F:phosphatase binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; IPI:UniProtKB.
DR GO; GO:0043276; P:anoikis; IGI:ParkinsonsUK-UCL.
DR GO; GO:0006897; P:endocytosis; TAS:ProtInc.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IBA:GO_Central.
DR GO; GO:1901525; P:negative regulation of mitophagy; NAS:ParkinsonsUK-UCL.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; ISS:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IDA:ComplexPortal.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0001843; P:neural tube closure; ISS:UniProtKB.
DR GO; GO:0050918; P:positive chemotaxis; ISS:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IEA:InterPro.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IGI:ParkinsonsUK-UCL.
DR GO; GO:0006606; P:protein import into nucleus; ISS:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0008104; P:protein localization; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
DR GO; GO:0030100; P:regulation of endocytosis; ISS:UniProtKB.
DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; IEA:InterPro.
DR GO; GO:0016192; P:vesicle-mediated transport; TAS:ProtInc.
DR Gene3D; 1.25.10.10; -; 1.
DR Gene3D; 3.40.50.11210; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR035974; Rap/Ran-GAP_sf.
DR InterPro; IPR000331; Rap/Ran_GAP_dom.
DR InterPro; IPR003913; Tuberin.
DR InterPro; IPR018515; Tuberin-type_domain.
DR InterPro; IPR027107; Tuberin/Ral-act_asu.
DR InterPro; IPR024584; Tuberin_N.
DR PANTHER; PTHR10063; PTHR10063; 3.
DR Pfam; PF11864; DUF3384; 1.
DR Pfam; PF02145; Rap_GAP; 1.
DR Pfam; PF03542; Tuberin; 1.
DR PRINTS; PR01431; TUBERIN.
DR SUPFAM; SSF111347; SSF111347; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50085; RAPGAP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; Epilepsy;
KW GTPase activation; Host-virus interaction; Membrane; Phosphoprotein;
KW Reference proteome; Tumor suppressor; Ubl conjugation.
FT CHAIN 1..1807
FT /note="Tuberin"
FT /id="PRO_0000065654"
FT DOMAIN 1531..1758
FT /note="Rap-GAP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00165"
FT REGION 1..400
FT /note="Required for interaction with TSC1"
FT REGION 655..676
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 930..964
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1083..1132
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1150..1174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1331..1352
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1364..1488
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1765..1793
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1083..1102
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1370..1394
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1469..1484
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 540
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18308511"
FT MOD_RES 664
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18308511"
FT MOD_RES 927
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 939
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:12150915,
FT ECO:0000269|PubMed:18308511"
FT MOD_RES 981
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1132
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692"
FT MOD_RES 1155
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 1271
FT /note="Phosphothreonine; by AMPK"
FT /evidence="ECO:0000269|PubMed:14651849"
FT MOD_RES 1337
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 1338
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 1346
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1364
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1387
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:14651849,
FT ECO:0000269|PubMed:15963462, ECO:0007744|PubMed:18669648"
FT MOD_RES 1411
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 1418
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15963462"
FT MOD_RES 1420
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15963462,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"
FT MOD_RES 1452
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1462
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:12150915,
FT ECO:0000269|PubMed:18308511, ECO:0007744|PubMed:19690332"
FT MOD_RES 1764
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q61037"
FT MOD_RES 1798
FT /note="Phosphoserine; by RPS6KA1"
FT /evidence="ECO:0000269|PubMed:15342917,
FT ECO:0000269|PubMed:18308511, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 1799
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..49
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054163"
FT VAR_SEQ 76..112
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_038355"
FT VAR_SEQ 113..239
FT /note="GERLGVLRALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELADFV
FT LQWMDVGLSSEFLLVLVNLVKFNSCYLDEYIARMVQMICLLCVRTASSVDIEVSLQVLD
FT AVVCYNCLPAESLPLF -> VRPRATLGWVTSGCPLTVLSLLGRVWTPASVSCWAQGLG
FT ADGLWSWMACGVSWCHEVCVTVGTASSPVNRWSLHLPLMGCSGDHMRQFSQSAEIVPGS
FT WCGATVLFCPCTLSGPLPCSLHSICAGLG (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:24722188"
FT /id="VSP_055896"
FT VAR_SEQ 240..1807
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:24722188"
FT /id="VSP_055897"
FT VAR_SEQ 946..989
FT /note="Missing (in isoform 3 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.7"
FT /id="VSP_004471"
FT VAR_SEQ 946..988
FT /note="Missing (in isoform 2, isoform 6 and isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_004470"
FT VAR_SEQ 1272..1294
FT /note="Missing (in isoform 4, isoform 5, isoform 6 and
FT isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|Ref.7"
FT /id="VSP_004472"
FT VARIANT 94
FT /note="P -> T (in dbSNP:rs1051616)"
FT /evidence="ECO:0000269|PubMed:8789450"
FT /id="VAR_008019"
FT VARIANT 137
FT /note="H -> R (in TSC2; unknown pathological significance;
FT dbSNP:rs45517107)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009415"
FT VARIANT 160
FT /note="L -> V (in dbSNP:rs45517109)"
FT /id="VAR_009416"
FT VARIANT 227
FT /note="C -> Y (in TSC2; dbSNP:rs45517122)"
FT /id="VAR_008020"
FT VARIANT 258
FT /note="K -> N (in TSC2; dbSNP:rs137854875)"
FT /id="VAR_009417"
FT VARIANT 261
FT /note="R -> P (in TSC2; dbSNP:rs45502703)"
FT /id="VAR_009418"
FT VARIANT 261
FT /note="R -> W (in dbSNP:rs45517130)"
FT /id="VAR_009419"
FT VARIANT 286
FT /note="M -> T (in dbSNP:rs45517136)"
FT /id="VAR_009420"
FT VARIANT 286
FT /note="M -> V (in dbSNP:rs1800748)"
FT /id="VAR_009421"
FT VARIANT 292
FT /note="L -> P (in TSC2; dbSNP:rs45517138)"
FT /id="VAR_005646"
FT VARIANT 294
FT /note="G -> E (in TSC2; dbSNP:rs45487497)"
FT /id="VAR_009422"
FT VARIANT 304
FT /note="W -> WGMALW (in TSC2)"
FT /id="VAR_009423"
FT VARIANT 309
FT /note="L -> Q (in dbSNP:rs137853986)"
FT /id="VAR_009424"
FT VARIANT 320
FT /note="L -> F (could be associated with TSC2;
FT dbSNP:rs1131825)"
FT /evidence="ECO:0000269|PubMed:10570911,
FT ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:8789450"
FT /id="VAR_009425"
FT VARIANT 331
FT /note="N -> K (in TSC2; dbSNP:rs45517153)"
FT /id="VAR_008021"
FT VARIANT 361
FT /note="L -> P (in TSC2; dbSNP:rs45517147)"
FT /id="VAR_009426"
FT VARIANT 365
FT /note="Missing (in TSC2; dbSNP:rs137854367)"
FT /id="VAR_009427"
FT VARIANT 367
FT /note="R -> Q (in dbSNP:rs1800725)"
FT /evidence="ECO:0000269|PubMed:15595939"
FT /id="VAR_009428"
FT VARIANT 378
FT /note="P -> L (in dbSNP:rs45517154)"
FT /id="VAR_009429"
FT VARIANT 407
FT /note="Y -> D (in TSC2; dbSNP:rs45517156)"
FT /id="VAR_005647"
FT VARIANT 440
FT /note="G -> S (in dbSNP:rs45484298)"
FT /id="VAR_009430"
FT VARIANT 449
FT /note="M -> I (in TSC2; dbSNP:rs45443091)"
FT /evidence="ECO:0000269|PubMed:8824881"
FT /id="VAR_005648"
FT VARIANT 463
FT /note="I -> V (in dbSNP:rs45517171)"
FT /id="VAR_009431"
FT VARIANT 486
FT /note="N -> I (in TSC2; dbSNP:rs45486599)"
FT /id="VAR_008022"
FT VARIANT 490
FT /note="I -> V (in dbSNP:rs45517175)"
FT /id="VAR_008023"
FT VARIANT 525
FT /note="N -> S (in TSC2; dbSNP:rs45457694)"
FT /id="VAR_009432"
FT VARIANT 536
FT /note="A -> V (in dbSNP:rs45517187)"
FT /id="VAR_008024"
FT VARIANT 583
FT /note="A -> T (in dbSNP:rs1800729)"
FT /id="VAR_009433"
FT VARIANT 593
FT /note="H -> R (in dbSNP:rs45517198)"
FT /id="VAR_009434"
FT VARIANT 599
FT /note="K -> M (in TSC2; impairs repression of EIF4EBP1
FT phosphorylation; dbSNP:rs45517202)"
FT /evidence="ECO:0000269|PubMed:12271141"
FT /id="VAR_009435"
FT VARIANT 607
FT /note="A -> T (in dbSNP:rs45517203)"
FT /evidence="ECO:0000269|PubMed:15024740"
FT /id="VAR_005649"
FT VARIANT 611
FT /note="R -> Q (in TSC2 and LAM; impairs phosphorylation at
FT S-1387, S-1418 and S-1420; enhances ubiquitination by
FT MYCBP2; dbSNP:rs28934872)"
FT /evidence="ECO:0000269|PubMed:10570911,
FT ECO:0000269|PubMed:10823953, ECO:0000269|PubMed:15595939,
FT ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:18308511"
FT /id="VAR_005650"
FT VARIANT 611
FT /note="R -> W (in TSC2; impairs phosphorylation at S-1387,
FT S-1418 and S-1420; dbSNP:rs45469298)"
FT /evidence="ECO:0000269|PubMed:10607950,
FT ECO:0000269|PubMed:15595939, ECO:0000269|PubMed:15963462,
FT ECO:0000269|PubMed:8824881"
FT /id="VAR_005651"
FT VARIANT 614
FT /note="A -> D (in TSC2; dbSNP:rs45454398)"
FT /id="VAR_009436"
FT VARIANT 615
FT /note="F -> S (in dbSNP:rs45481105)"
FT /id="VAR_008025"
FT VARIANT 619
FT /note="L -> F (in dbSNP:rs1131826)"
FT /evidence="ECO:0000269|PubMed:8789450"
FT /id="VAR_060584"
FT VARIANT 647
FT /note="D -> N (in TSC2; unknown pathological significance;
FT dbSNP:rs45509392)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009437"
FT VARIANT 694
FT /note="Missing (in TSC2)"
FT /id="VAR_009438"
FT VARIANT 696
FT /note="C -> Y (in TSC2; dbSNP:rs45486196)"
FT /id="VAR_009439"
FT VARIANT 717
FT /note="L -> R (in TSC2; dbSNP:rs45517214)"
FT /evidence="ECO:0000269|PubMed:10069705,
FT ECO:0000269|PubMed:10570911"
FT /id="VAR_009440"
FT VARIANT 769
FT /note="V -> E (in TSC2; unknown pathological significance;
FT dbSNP:rs45499191)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009441"
FT VARIANT 802
FT /note="S -> R (in dbSNP:rs1051621)"
FT /evidence="ECO:0000269|PubMed:8269512,
FT ECO:0000269|PubMed:8789450"
FT /id="VAR_060585"
FT VARIANT 816
FT /note="P -> L (in TSC2; dbSNP:rs45517236)"
FT /id="VAR_008026"
FT VARIANT 826
FT /note="L -> M (in TSC2; dbSNP:rs45517238)"
FT /id="VAR_005652"
FT VARIANT 862
FT /note="A -> V (in dbSNP:rs45517249)"
FT /evidence="ECO:0000269|PubMed:15024740"
FT /id="VAR_018600"
FT VARIANT 895
FT /note="M -> V (in TSC2; dbSNP:rs45470695)"
FT /id="VAR_009442"
FT VARIANT 905
FT /note="R -> Q (in TSC2; dbSNP:rs45517259)"
FT /id="VAR_005653"
FT VARIANT 905
FT /note="R -> W (in TSC2; dbSNP:rs45517258)"
FT /evidence="ECO:0000269|PubMed:10607950"
FT /id="VAR_005654"
FT VARIANT 963
FT /note="V -> M (in TSC2; unknown pathological significance;
FT dbSNP:rs45517275)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009443"
FT VARIANT 1027
FT /note="L -> P (in TSC2; dbSNP:rs45438192)"
FT /evidence="ECO:0000269|PubMed:15595939"
FT /id="VAR_022919"
FT VARIANT 1084
FT /note="D -> E (in TSC2; dbSNP:rs45517286)"
FT /id="VAR_005655"
FT VARIANT 1141
FT /note="A -> V (in dbSNP:rs34870424)"
FT /id="VAR_057014"
FT VARIANT 1144
FT /note="V -> M (in TSC2; dbSNP:rs45517294)"
FT /id="VAR_008027"
FT VARIANT 1200
FT /note="R -> W (in TSC2; dbSNP:rs45438205)"
FT /id="VAR_005656"
FT VARIANT 1227
FT /note="P -> L (in TSC2)"
FT /evidence="ECO:0000269|PubMed:8824881"
FT /id="VAR_005657"
FT VARIANT 1240
FT /note="R -> W (in TSC2)"
FT /evidence="ECO:0000269|PubMed:8824881"
FT /id="VAR_005658"
FT VARIANT 1282
FT /note="S -> G (in dbSNP:rs45446700)"
FT /id="VAR_009444"
FT VARIANT 1295
FT /note="D -> V (in TSC2)"
FT /id="VAR_005659"
FT VARIANT 1315
FT /note="P -> S (in TSC2; dbSNP:rs397514916)"
FT /id="VAR_008028"
FT VARIANT 1329
FT /note="R -> H (in dbSNP:rs45517323)"
FT /id="VAR_008029"
FT VARIANT 1341
FT /note="S -> R (in dbSNP:rs45462593)"
FT /evidence="ECO:0000269|PubMed:15595939"
FT /id="VAR_022920"
FT VARIANT 1429
FT /note="A -> S (in dbSNP:rs45474795)"
FT /evidence="ECO:0000269|PubMed:15024740"
FT /id="VAR_018601"
FT VARIANT 1450
FT /note="P -> R (in dbSNP:rs45517338)"
FT /evidence="ECO:0000269|PubMed:15024740"
FT /id="VAR_018602"
FT VARIANT 1497
FT /note="P -> R (in TSC2; dbSNP:rs45497997)"
FT /id="VAR_009445"
FT VARIANT 1498
FT /note="S -> N (in TSC2; dbSNP:rs137854879)"
FT /id="VAR_009446"
FT VARIANT 1509
FT /note="Missing (in TSC2; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:8824881,
FT ECO:0000269|PubMed:9302281"
FT /id="VAR_005660"
FT VARIANT 1547
FT /note="V -> I (in FCORD2; somatic mutation; decreased
FT function in negative regulation of TOR signaling; does not
FT affect interaction with TSC1; dbSNP:rs745895675)"
FT /evidence="ECO:0000269|PubMed:28215400"
FT /id="VAR_078847"
FT VARIANT 1549
FT /note="Y -> C (in TSC2; dbSNP:rs45517355)"
FT /id="VAR_005661"
FT VARIANT 1594
FT /note="L -> M (in TSC2; unknown pathological significance;
FT dbSNP:rs45511204)"
FT /evidence="ECO:0000269|PubMed:9302281"
FT /id="VAR_009447"
FT VARIANT 1614
FT /note="Missing (in TSC2)"
FT /id="VAR_005662"
FT VARIANT 1620
FT /note="H -> Y (in TSC2; dbSNP:rs45446901)"
FT /id="VAR_009448"
FT VARIANT 1636
FT /note="D -> N (in dbSNP:rs45482398)"
FT /evidence="ECO:0000269|PubMed:15595939"
FT /id="VAR_022921"
FT VARIANT 1643
FT /note="N -> I (in TSC2; dbSNP:rs45517380)"
FT /id="VAR_005663"
FT VARIANT 1643
FT /note="N -> K (in TSC2; Abolishes GAP activity;
FT dbSNP:rs45517381)"
FT /evidence="ECO:0000269|PubMed:15340059,
FT ECO:0000269|PubMed:9302281"
FT /id="VAR_009449"
FT VARIANT 1650
FT /note="Y -> C (in TSC2; dbSNP:rs45501091)"
FT /id="VAR_005664"
FT VARIANT 1651
FT /note="N -> S (in TSC2; greatly reduces the ability to
FT enhance the RHEB GTPase activity; dbSNP:rs45517382)"
FT /evidence="ECO:0000269|PubMed:12271141,
FT ECO:0000269|PubMed:15024740, ECO:0000269|PubMed:15340059,
FT ECO:0000269|PubMed:9302281"
FT /id="VAR_009450"
FT VARIANT 1653
FT /note="S -> F (in TSC2; dbSNP:rs45517383)"
FT /evidence="ECO:0000269|PubMed:15024740"
FT /id="VAR_018603"
FT VARIANT 1673
FT /note="V -> L (in dbSNP:rs45490993)"
FT /evidence="ECO:0000269|PubMed:15595939"
FT /id="VAR_022922"
FT VARIANT 1675
FT /note="P -> L (in TSC2; dbSNP:rs45483392)"
FT /evidence="ECO:0000269|PubMed:10570911,
FT ECO:0000269|PubMed:15024740, ECO:0000269|PubMed:9302281"
FT /id="VAR_009451"
FT VARIANT 1681
FT /note="N -> K (in TSC2; Abolishes GAP activity;
FT dbSNP:rs45476793)"
FT /evidence="ECO:0000269|PubMed:15340059,
FT ECO:0000269|PubMed:9302281"
FT /id="VAR_009452"
FT VARIANT 1690
FT /note="D -> Y (in TSC2; dbSNP:rs137854882)"
FT /id="VAR_005665"
FT VARIANT 1704
FT /note="S -> T (in TSC2; dbSNP:rs45474691)"
FT /id="VAR_009453"
FT VARIANT 1709
FT /note="P -> L (in TSC2; dbSNP:rs45517393)"
FT /id="VAR_008030"
FT VARIANT 1712
FT /note="A -> E (in TSC2)"
FT /evidence="ECO:0000269|PubMed:8824881"
FT /id="VAR_005666"
FT VARIANT 1743
FT /note="R -> P (in TSC2; Abolishes GAP activity;
FT dbSNP:rs45507199)"
FT /evidence="ECO:0000269|PubMed:15340059"
FT /id="VAR_009454"
FT VARIANT 1743
FT /note="R -> Q (in TSC2; dbSNP:rs45507199)"
FT /id="VAR_008031"
FT VARIANT 1744
FT /note="L -> P (in TSC2; dbSNP:rs45517413)"
FT /evidence="ECO:0000269|PubMed:10607950"
FT /id="VAR_009455"
FT VARIANT 1746..1751
FT /note="Missing (in TSC2)"
FT /evidence="ECO:0000269|PubMed:10607950,
FT ECO:0000269|PubMed:15024740"
FT /id="VAR_009456"
FT VARIANT 1750
FT /note="L -> F (in TSC2; dbSNP:rs45459299)"
FT /id="VAR_005667"
FT VARIANT 1773
FT /note="H -> P (in TSC2; dbSNP:rs45517418)"
FT /id="VAR_008032"
FT VARIANT 1774
FT /note="S -> T (in dbSNP:rs9209)"
FT /id="VAR_057015"
FT VARIANT 1783
FT /note="E -> Q (in TSC2; dbSNP:rs777166275)"
FT /id="VAR_008033"
FT VARIANT 1787
FT /note="G -> S (in dbSNP:rs45517419)"
FT /id="VAR_009457"
FT VARIANT 1791
FT /note="G -> S (in dbSNP:rs45517421)"
FT /id="VAR_009458"
FT MUTAGEN 939
FT /note="S->A: Inhibits insulin-stimulated phosphorylation
FT and activation of S6K1; when associated with A-1462."
FT MUTAGEN 1271
FT /note="T->A: Abolishes AMPK-mediated phosphorylation; when
FT associated with A-1387."
FT /evidence="ECO:0000269|PubMed:14651849"
FT MUTAGEN 1387
FT /note="S->A: Abolishes AMPK-mediated phosphorylation; when
FT associated with A-1271."
FT /evidence="ECO:0000269|PubMed:14651849"
FT MUTAGEN 1462
FT /note="T->A: Inhibits insulin-stimulated phosphorylation
FT and activation of S6K1; when associated with A-939."
FT MUTAGEN 1637..1639
FT /note="KKR->QQQ: Abolishes GAP activity."
FT /evidence="ECO:0000269|PubMed:15340059"
FT MUTAGEN 1745
FT /note="R->Q: Abolishes GAP activity."
FT /evidence="ECO:0000269|PubMed:15340059"
FT MUTAGEN 1749..1751
FT /note="RLR->QLQ: No effect."
FT /evidence="ECO:0000269|PubMed:15340059"
FT CONFLICT 187
FT /note="N -> S (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
FT CONFLICT 210
FT /note="A -> V (in Ref. 10; AAI50301)"
FT /evidence="ECO:0000305"
FT CONFLICT 335
FT /note="S -> P (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
FT CONFLICT 392
FT /note="E -> V (in Ref. 7; BAG58569)"
FT /evidence="ECO:0000305"
FT CONFLICT 422
FT /note="S -> P (in Ref. 7; BAG58569)"
FT /evidence="ECO:0000305"
FT CONFLICT 660
FT /note="S -> N (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
FT CONFLICT 704
FT /note="K -> E (in Ref. 10; AAI50301)"
FT /evidence="ECO:0000305"
FT CONFLICT 706
FT /note="L -> P (in Ref. 7; BAG58569)"
FT /evidence="ECO:0000305"
FT CONFLICT 1015
FT /note="L -> M (in Ref. 10; AAI50301)"
FT /evidence="ECO:0000305"
FT CONFLICT 1239
FT /note="E -> V (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
FT CONFLICT 1398
FT /note="L -> V (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
FT CONFLICT 1672
FT /note="I -> M (in Ref. 10; AAI50301)"
FT /evidence="ECO:0000305"
FT CONFLICT 1807
FT /note="V -> A (in Ref. 7; BAG61344)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1807 AA; 200608 MW; 7B915C46970D7D31 CRC64;
MAKPTSKDSG LKEKFKILLG LGTPRPNPRS AEGKQTEFII TAEILRELSM ECGLNNRIRM
IGQICEVAKT KKFEEHAVEA LWKAVADLLQ PERPLEARHA VLALLKAIVQ GQGERLGVLR
ALFFKVIKDY PSNEDLHERL EVFKALTDNG RHITYLEEEL ADFVLQWMDV GLSSEFLLVL
VNLVKFNSCY LDEYIARMVQ MICLLCVRTA SSVDIEVSLQ VLDAVVCYNC LPAESLPLFI
VTLCRTINVK ELCEPCWKLM RNLLGTHLGH SAIYNMCHLM EDRAYMEDAP LLRGAVFFVG
MALWGAHRLY SLRNSPTSVL PSFYQAMACP NEVVSYEIVL SITRLIKKYR KELQVVAWDI
LLNIIERLLQ QLQTLDSPEL RTIVHDLLTT VEELCDQNEF HGSQERYFEL VERCADQRPE
SSLLNLISYR AQSIHPAKDG WIQNLQALME RFFRSESRGA VRIKVLDVLS FVLLINRQFY
EEELINSVVI SQLSHIPEDK DHQVRKLATQ LLVDLAEGCH THHFNSLLDI IEKVMARSLS
PPPELEERDV AAYSASLEDV KTAVLGLLVI LQTKLYTLPA SHATRVYEML VSHIQLHYKH
SYTLPIASSI RLQAFDFLLL LRADSLHRLG LPNKDGVVRF SPYCVCDYME PERGSEKKTS
GPLSPPTGPP GPAPAGPAVR LGSVPYSLLF RVLLQCLKQE SDWKVLKLVL GRLPESLRYK
VLIFTSPCSV DQLCSALCSM LSGPKTLERL RGAPEGFSRT DLHLAVVPVL TALISYHNYL
DKTKQREMVY CLEQGLIHRC ASQCVVALSI CSVEMPDIII KALPVLVVKL THISATASMA
VPLLEFLSTL ARLPHLYRNF AAEQYASVFA ISLPYTNPSK FNQYIVCLAH HVIAMWFIRC
RLPFRKDFVP FITKGLRSNV LLSFDDTPEK DSFRARSTSL NERPKSLRIA RPPKQGLNNS
PPVKEFKESS AAEAFRCRSI SVSEHVVRSR IQTSLTSASL GSADENSVAQ ADDSLKNLHL
ELTETCLDMM ARYVFSNFTA VPKRSPVGEF LLAGGRTKTW LVGNKLVTVT TSVGTGTRSL
LGLDSGELQS GPESSSSPGV HVRQTKEAPA KLESQAGQQV SRGARDRVRS MSGGHGLRVG
ALDVPASQFL GSATSPGPRT APAAKPEKAS AGTRVPVQEK TNLAAYVPLL TQGWAEILVR
RPTGNTSWLM SLENPLSPFS SDINNMPLQE LSNALMAAER FKEHRDTALY KSLSVPAAST
AKPPPLPRSN TVASFSSLYQ SSCQGQLHRS VSWADSAVVM EEGSPGEVPV LVEPPGLEDV
EAALGMDRRT DAYSRSSSVS SQEEKSLHAE ELVGRGIPIE RVVSSEGGRP SVDLSFQPSQ
PLSKSSSSPE LQTLQDILGD PGDKADVGRL SPEVKARSQS GTLDGESAAW SASGEDSRGQ
PEGPLPSSSP RSPSGLRPRG YTISDSAPSR RGKRVERDAL KSRATASNAE KVPGINPSFV
FLQLYHSPFF GDESNKPILL PNESQSFERS VQLLDQIPSY DTHKIAVLYV GEGQSNSELA
ILSNEHGSYR YTEFLTGLGR LIELKDCQPD KVYLGGLDVC GEDGQFTYCW HDDIMQAVFH
IATLMPTKDV DKHRCDKKRH LGNDFVSIVY NDSGEDFKLG TIKGQFNFVH VIVTPLDYEC
NLVSLQCRKD MEGLVDTSVA KIVSDRNLPF VARQMALHAN MASQVHHSRS NPTDIYPSKW
IARLRHIKRL RQRICEEAAY SNPSLPLVHP PSHSKAPAQT PAEPTPGYEV GQRKRLISSV
EDFTEFV
