TSC1_HUMAN
ID TSC1_HUMAN Reviewed; 1164 AA.
AC Q92574; B7Z897; Q5VVN5;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 2.
DT 03-AUG-2022, entry version 208.
DE RecName: Full=Hamartin;
DE AltName: Full=Tuberous sclerosis 1 protein;
GN Name=TSC1; Synonyms=KIAA0243, TSC;
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-587.
RX PubMed=9242607; DOI=10.1126/science.277.5327.805;
RA van Slegtenhorst M.A., de Hoogt R., Hermans C., Nellist M., Janssen B.,
RA Verhoef S., Lindhout D., van den Ouweland A.M.W., Halley D.J.J., Young J.,
RA Burley M., Jeremiah S., Woodward K., Nahmias J., Fox M., Ekong R.,
RA Osborne J., Wolfe J., Povey S., Snell R.G., Cheadle J.P., Jones A.C.,
RA Tachataki M., Ravine D., Sampson J.R., Reeve M.P., Richardson P.,
RA Wilmer F., Munro C., Hawkins T.L., Sepp T., Ali J.B.M., Ward S.,
RA Green A.J., Yates J.R.W., Kwiatkowska J., Henske E.P., Short M.P.,
RA Haines J.H., Jozwiak S., Kwiatkowski D.J.;
RT "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.";
RL Science 277:805-808(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 466-1164 (ISOFORM 1/2).
RC TISSUE=Bone marrow;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 568-586.
RA Fang L., Wang N., Murong S.X., Wu Z.Y., Lin M.T.;
RT "A silent mutation 1947 T-->C in exon 15 of TSC1 in Chinese.";
RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH TSC2.
RX PubMed=9809973;
RA Plank T.L., Yeung R.S., Henske E.P.;
RT "Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts
RT with tuberin and appears to be localized to cytoplasmic vesicles.";
RL Cancer Res. 58:4766-4770(1998).
RN [8]
RP INTERACTION WITH TSC2.
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 [9]
RP INTERACTION WITH TSC2.
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 [10]
RP INVOLVEMENT IN LAM, AND VARIANT TSC1 165-CYS--SER-1164 DEL.
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 [11]
RP FUNCTION.
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 [12]
RP FUNCTION.
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 [13]
RP PHOSPHORYLATION AT SER-505, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP INTERACTION WITH DOCK7 AND TSC2.
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 [14]
RP FUNCTION, AND INTERACTION WITH TSC2.
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 [15]
RP INTERACTION WITH TBC1D7.
RX PubMed=17658474; DOI=10.1016/j.bbrc.2007.07.011;
RA Nakashima A., Yoshino K., Miyamoto T., Eguchi S., Oshiro N., Kikkawa U.,
RA Yonezawa K.;
RT "Identification of TBC7 having TBC domain as a novel binding protein to
RT TSC1-TSC2 complex.";
RL Biochem. Biophys. Res. Commun. 361:218-223(2007).
RN [16]
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, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA 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 [17]
RP 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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505; SER-511 AND SER-598, AND
RP 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 [20]
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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505, AND IDENTIFICATION BY
RP 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 [22]
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 [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-487; SER-505 AND SER-521, AND
RP IDENTIFICATION BY MASS 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 [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1100, 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 [25]
RP FUNCTION, INTERACTION WITH TSC2, INVOLVEMENT IN FCORD2, VARIANTS FCORD2
RP TRP-22 AND CYS-204, AND CHARACTERIZATION OF VARIANTS FCORD2 TRP-22 AND
RP CYS-204.
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 [26]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; STIP1; CDC37;
RP PPP5C; PTGES3; TSC2; AKT; CDK4; RAF1 AND NR3C1, INTERACTION WITH HSP90AA1
RP AND TSC2, AND VARIANT PRO-117.
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 [27]
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 [28]
RP INTERACTION WITH WDR45B, AND REGION.
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 [29]
RP VARIANT TSC1 GLU-726, AND VARIANTS THR-322; TYR-732 AND SER-1035.
RC TISSUE=Peripheral blood;
RX PubMed=9328481; DOI=10.1093/hmg/6.12.2155;
RA Jones A.C., Daniells C.E., Snell R.G., Tachataki M., Idziaszczyk S.A.,
RA Krawczak M., Sampson J.R., Cheadle J.P.;
RT "Molecular genetic and phenotypic analysis reveals differences between TSC1
RT and TSC2 associated familial and sporadic tuberous sclerosis.";
RL Hum. Mol. Genet. 6:2155-2161(1997).
RN [30]
RP VARIANTS THR-322; ARG-587; TYR-732; SER-1035 AND SER-1108.
RC TISSUE=Blood;
RX PubMed=9924605; DOI=10.1046/j.1469-1809.1998.6240277.x;
RA Kwiatkowska J., Jozwiak S., Hall F., Henske E.P., Haines J.L., McNamara P.,
RA Braiser J., Wigowska-Sowinska J., Kasprzyk-Obara J., Short M.P.,
RA Kwiatkowski D.J.;
RT "Comprehensive mutational analysis of the TSC1 gene: observations on
RT frequency of mutation, associated features, and nonpenetrance.";
RL Ann. Hum. Genet. 62:277-285(1998).
RN [31]
RP VARIANT TSC1 PRO-72.
RX PubMed=10533069;
RX DOI=10.1002/(sici)1098-1004(199911)14:5<428::aid-humu9>3.0.co;2-5;
RA Benit P., Kara-Mostefa A., Hadj-Rabia S., Munnich A., Bonnefont J.-P.;
RT "Protein truncation test for screening hamartin gene mutations and report
RT of new disease-causing mutations.";
RL Hum. Mutat. 14:428-432(1999).
RN [32]
RP VARIANTS THR-322; TYR-732 AND GLN-809.
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 [33]
RP VARIANTS TSC1 ILE-417; GLU-654 AND SER-899, AND VARIANT THR-322.
RC TISSUE=Blood;
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 [34]
RP VARIANTS TSC1, AND VARIANTS.
RC TISSUE=Peripheral blood;
RX PubMed=10227394;
RA Van Slegtenhorst M.A., Verhoef S., Tempelaars A., Bakker L., Wang Q.,
RA Wessels M., Bakker R., Nellist M., Lindhout D., Halley D.J.J.,
RA van den Ouweland A.M.W.;
RT "Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis
RT complex patients: no evidence for genotype-phenotype correlation.";
RL J. Med. Genet. 36:285-289(1999).
RN [35]
RP VARIANTS THR-322; ILE-417; ASP-577 AND ARG-829.
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 [36]
RP VARIANT TSC1 GLN-500.
RX PubMed=10874311;
RX DOI=10.1002/1098-1004(200007)16:1<88::aid-humu15>3.0.co;2-j;
RA Hass J., Mayer K., Rott H.-D.;
RT "Tuberous sclerosis type 1: three novel mutations detected in exon 15 by a
RT combination of HDA and TGGE.";
RL Hum. Mutat. 16:88-88(2000).
RN [37]
RP VARIANT TYR-732.
RX PubMed=12112044; DOI=10.1002/ana.10251;
RA Becker A.J., Urbach H., Scheffler B., Baden T., Normann S., Lahl R.,
RA Pannek H.W., Tuxhorn I., Elger C.E., Schramm J., Wiestler O.D.,
RA Bluemcke I.;
RT "Focal cortical dysplasia of Taylor's balloon cell type: mutational
RT analysis of the TSC1 gene indicates a pathogenic relationship to tuberous
RT sclerosis.";
RL Ann. Neurol. 52:29-37(2002).
RN [38]
RP VARIANTS ARG-68; CYS-158; ASP-206; LEU-216 AND ILE-417, AND
RP CHARACTERIZATION OF VARIANTS ARG-68; CYS-158; ASP-206; LEU-216 AND ILE-417.
RX PubMed=18397877; DOI=10.1093/hmg/ddn098;
RA Pymar L.S., Platt F.M., Askham J.M., Morrison E.E., Knowles M.A.;
RT "Bladder tumour-derived somatic TSC1 missense mutations cause loss of
RT function via distinct mechanisms.";
RL Hum. Mol. Genet. 17:2006-2017(2008).
RN [39]
RP VARIANTS TSC1 PRO-117; VAL-128 DEL; PRO-180; HIS-191; 198-ASN-PHE-199
RP DELINS ILE; ARG-224; LYS-246; ARG-305 AND TRP-305, VARIANTS GLN-509;
RP SER-1035 AND HIS-1097, CHARACTERIZATION OF VARIANTS TSC1 PRO-117; VAL-128
RP DEL; PRO-180; HIS-191; 198-ASN-PHE-199 DELINS ILE; ARG-224; LYS-246;
RP ARG-305 AND TRP-305, AND CHARACTERIZATION OF VARIANTS GLN-509; SER-1035 AND
RP HIS-1097.
RX PubMed=18830229; DOI=10.1038/ejhg.2008.170;
RA Nellist M., van den Heuvel D., Schluep D., Exalto C., Goedbloed M.,
RA Maat-Kievit A., van Essen T., van Spaendonck-Zwarts K., Jansen F.,
RA Helderman P., Bartalini G., Vierimaa O., Penttinen M., van den Ende J.,
RA van den Ouweland A., Halley D.;
RT "Missense mutations to the TSC1 gene cause tuberous sclerosis complex.";
RL Eur. J. Hum. Genet. 17:319-328(2009).
RN [40]
RP VARIANTS TSC1 ARG-61; ILE-126; ASP-132; ILE-133; GLN-336; SER-362; ILE-411;
RP PRO-523; HIS-693; ARG-698; HIS-701; SER-762; GLY-811; THR-883; VAL-978;
RP SER-1043 DEL AND TYR-1146, VARIANTS SER-158; PRO-204; SER-448 AND VAL-567,
RP CHARACTERIZATION OF VARIANTS TSC1 ARG-61; PRO-117; ILE-126; ASP-132;
RP ILE-133; GLN-336; SER-362; ILE-411; PRO-523; HIS-693; ARG-698; HIS-701;
RP SER-762; GLY-811; THR-883; VAL-978; SER-1043 DEL AND TYR-1146, AND
RP CHARACTERIZATION OF VARIANTS SER-158; PRO-204; SER-448 AND VAL-567.
RX PubMed=22161988; DOI=10.1002/humu.22007;
RA Hoogeveen-Westerveld M., Ekong R., Povey S., Karbassi I., Batish S.D.,
RA den Dunnen J.T., van Eeghen A., Thiele E., Mayer K., Dies K., Wen L.,
RA Thompson C., Sparagana S.P., Davies P., Aalfs C., van den Ouweland A.,
RA Halley D., Nellist M.;
RT "Functional assessment of TSC1 missense variants identified in individuals
RT with tuberous sclerosis complex.";
RL Hum. Mutat. 33:476-479(2012).
CC -!- FUNCTION: In complex with TSC2, inhibits the nutrient-mediated or
CC growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by
CC negatively regulating mTORC1 signaling (PubMed:12271141,
CC PubMed:28215400). Seems not to be required for TSC2 GAP activity
CC towards RHEB (PubMed:15340059). Implicated as a tumor suppressor.
CC Involved in microtubule-mediated protein transport, but this seems to
CC be due to unregulated mTOR signaling (By similarity). Acts as a co-
CC chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein
CC clients such as kinases, TSC2 and glucocorticoid receptor NR3C1
CC (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits
CC HSP90AA1 ATPase activity (PubMed:29127155). Competes with the
CC activating co-chaperone AHSA1 for binding to HSP90AA1, thereby
CC providing a reciprocal regulatory mechanism for chaperoning of client
CC proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes
CC TSC2 by preventing the interaction between TSC2 and ubiquitin ligase
CC HERC1 (PubMed:16464865, PubMed:29127155).
CC {ECO:0000250|UniProtKB:Q9Z136, ECO:0000269|PubMed:12271141,
CC ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:16464865,
CC ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:29127155}.
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). Forms a complex composed of
CC chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client
CC protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain
CC co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a
CC complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit
CC TCS2 to the complex (PubMed:29127155). Interacts (via C-terminus) with
CC the closed form of HSP90AA1 (via the middle domain and TPR repeat-
CC binding motif) (PubMed:29127155). Interacts with TSC2; the interaction
CC stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443,
CC PubMed:15963462, PubMed:16464865, PubMed:9580671, PubMed:9809973,
CC PubMed:29127155, PubMed:28215400). Interacts with DOCK7
CC (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts
CC with TBC1D7 (PubMed:17658474). Interacts with WDR45B (PubMed:28561066).
CC Interacts with RPAP3 and URI1 (PubMed:28561026).
CC {ECO:0000269|PubMed:10585443, ECO:0000269|PubMed:15963462,
CC ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:17658474,
CC ECO:0000269|PubMed:18381890, ECO:0000269|PubMed:28215400,
CC ECO:0000269|PubMed:28561026, ECO:0000269|PubMed:28561066,
CC ECO:0000269|PubMed:29127155, ECO:0000269|PubMed:9580671,
CC ECO:0000269|PubMed:9809973}.
CC -!- INTERACTION:
CC Q92574; Q00994: BEX3; NbExp=5; IntAct=EBI-1047085, EBI-741753;
CC Q92574; P02794: FTH1; NbExp=3; IntAct=EBI-1047085, EBI-713259;
CC Q92574; O14920: IKBKB; NbExp=3; IntAct=EBI-1047085, EBI-81266;
CC Q92574; Q674X7: KAZN; NbExp=2; IntAct=EBI-1047085, EBI-949239;
CC Q92574; Q16539: MAPK14; NbExp=2; IntAct=EBI-1047085, EBI-73946;
CC Q92574; Q9NRD5: PICK1; NbExp=2; IntAct=EBI-1047085, EBI-79165;
CC Q92574; Q92844: TANK; NbExp=3; IntAct=EBI-1047085, EBI-356349;
CC Q92574; P49815: TSC2; NbExp=11; IntAct=EBI-1047085, EBI-396587;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9809973}. Membrane
CC {ECO:0000269|PubMed:9809973}; Peripheral membrane protein
CC {ECO:0000269|PubMed:9809973}. Note=At steady state found in association
CC with membranes. {ECO:0000269|PubMed:9809973}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q92574-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92574-2; Sequence=VSP_042890;
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, followed by
CC heart, brain, placenta, pancreas, lung, liver and kidney. Also
CC expressed in embryonic kidney cells.
CC -!- DOMAIN: The C-terminal putative coiled-coil domain is necessary for
CC interaction with TSC2. {ECO:0000269|PubMed:9580671}.
CC -!- PTM: Phosphorylation at Ser-505 does not affect interaction with TSC2.
CC {ECO:0000269|PubMed:15963462}.
CC -!- DISEASE: Tuberous sclerosis 1 (TSC1) [MIM:191100]: 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:10227394,
CC ECO:0000269|PubMed:10533069, ECO:0000269|PubMed:10570911,
CC ECO:0000269|PubMed:10874311, ECO:0000269|PubMed:11829138,
CC ECO:0000269|PubMed:18830229, ECO:0000269|PubMed:22161988,
CC ECO:0000269|PubMed:9328481}. 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:11829138}. Note=The disease is caused by variants
CC affecting the gene represented in this 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 -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TSC1ID183.html";
CC -!- WEB RESOURCE: Name=Tuberous sclerosis database Tuberous sclerosis 1
CC (TSC1); Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/TSC1";
CC ---------------------------------------------------------------------------
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DR EMBL; AF013168; AAC51674.1; -; mRNA.
DR EMBL; AK303030; BAH13883.1; -; mRNA.
DR EMBL; AL445645; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471090; EAW88021.1; -; Genomic_DNA.
DR EMBL; AC002096; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; D87683; BAA13436.1; -; mRNA.
DR EMBL; AF234185; AAF61948.1; -; Genomic_DNA.
DR CCDS; CCDS55350.1; -. [Q92574-2]
DR CCDS; CCDS6956.1; -. [Q92574-1]
DR PIR; T03814; T03814.
DR RefSeq; NP_000359.1; NM_000368.4. [Q92574-1]
DR RefSeq; NP_001155898.1; NM_001162426.1.
DR RefSeq; NP_001155899.1; NM_001162427.1. [Q92574-2]
DR RefSeq; XP_005272268.1; XM_005272211.1. [Q92574-1]
DR RefSeq; XP_006717334.1; XM_006717271.1. [Q92574-1]
DR RefSeq; XP_011517281.1; XM_011518979.2. [Q92574-1]
DR RefSeq; XP_016870585.1; XM_017015096.1. [Q92574-1]
DR RefSeq; XP_016870586.1; XM_017015097.1. [Q92574-1]
DR PDB; 4Z6Y; X-ray; 2.81 A; C/D/F/H=938-993.
DR PDB; 5EJC; X-ray; 3.10 A; C/D/E/F=939-992.
DR PDB; 7DL2; EM; 4.40 A; C/D=1-1164.
DR PDBsum; 4Z6Y; -.
DR PDBsum; 5EJC; -.
DR PDBsum; 7DL2; -.
DR AlphaFoldDB; Q92574; -.
DR SMR; Q92574; -.
DR BioGRID; 113099; 268.
DR ComplexPortal; CPX-6142; TSC1-TSC2 complex.
DR CORUM; Q92574; -.
DR IntAct; Q92574; 126.
DR MINT; Q92574; -.
DR STRING; 9606.ENSP00000298552; -.
DR CarbonylDB; Q92574; -.
DR GlyGen; Q92574; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q92574; -.
DR PhosphoSitePlus; Q92574; -.
DR BioMuta; TSC1; -.
DR DMDM; 9297077; -.
DR EPD; Q92574; -.
DR jPOST; Q92574; -.
DR MassIVE; Q92574; -.
DR MaxQB; Q92574; -.
DR PaxDb; Q92574; -.
DR PeptideAtlas; Q92574; -.
DR PRIDE; Q92574; -.
DR ProteomicsDB; 75334; -. [Q92574-1]
DR ProteomicsDB; 75335; -. [Q92574-2]
DR Antibodypedia; 3164; 1882 antibodies from 46 providers.
DR DNASU; 7248; -.
DR Ensembl; ENST00000298552.9; ENSP00000298552.3; ENSG00000165699.15. [Q92574-1]
DR Ensembl; ENST00000440111.6; ENSP00000394524.2; ENSG00000165699.15. [Q92574-1]
DR Ensembl; ENST00000545250.5; ENSP00000444017.1; ENSG00000165699.15. [Q92574-2]
DR Ensembl; ENST00000643072.1; ENSP00000496691.1; ENSG00000165699.15. [Q92574-2]
DR Ensembl; ENST00000643875.1; ENSP00000495158.1; ENSG00000165699.15. [Q92574-1]
DR Ensembl; ENST00000646625.1; ENSP00000496263.1; ENSG00000165699.15. [Q92574-1]
DR GeneID; 7248; -.
DR KEGG; hsa:7248; -.
DR MANE-Select; ENST00000298552.9; ENSP00000298552.3; NM_000368.5; NP_000359.1.
DR UCSC; uc064wss.1; human. [Q92574-1]
DR CTD; 7248; -.
DR DisGeNET; 7248; -.
DR GeneCards; TSC1; -.
DR GeneReviews; TSC1; -.
DR HGNC; HGNC:12362; TSC1.
DR HPA; ENSG00000165699; Low tissue specificity.
DR MalaCards; TSC1; -.
DR MIM; 191100; phenotype.
DR MIM; 605284; gene.
DR MIM; 606690; phenotype.
DR MIM; 607341; phenotype.
DR neXtProt; NX_Q92574; -.
DR OpenTargets; ENSG00000165699; -.
DR Orphanet; 210159; Adult hepatocellular carcinoma.
DR Orphanet; 269008; Isolated focal cortical dysplasia type IIb.
DR Orphanet; 538; Lymphangioleiomyomatosis.
DR Orphanet; 805; Tuberous sclerosis complex.
DR PharmGKB; PA37034; -.
DR VEuPathDB; HostDB:ENSG00000165699; -.
DR eggNOG; ENOG502QQPT; Eukaryota.
DR GeneTree; ENSGT00390000014148; -.
DR HOGENOM; CLU_011546_0_0_1; -.
DR InParanoid; Q92574; -.
DR OMA; NRMASYS; -.
DR PhylomeDB; Q92574; -.
DR TreeFam; TF325466; -.
DR PathwayCommons; Q92574; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR Reactome; R-HSA-165181; Inhibition of TSC complex formation by PKB.
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-8854214; TBC/RABGAPs.
DR SABIO-RK; Q92574; -.
DR SignaLink; Q92574; -.
DR SIGNOR; Q92574; -.
DR BioGRID-ORCS; 7248; 84 hits in 1100 CRISPR screens.
DR ChiTaRS; TSC1; human.
DR GeneWiki; TSC1; -.
DR GenomeRNAi; 7248; -.
DR Pharos; Q92574; Tbio.
DR PRO; PR:Q92574; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q92574; protein.
DR Bgee; ENSG00000165699; Expressed in substantia nigra pars compacta and 212 other tissues.
DR ExpressionAtlas; Q92574; baseline and differential.
DR Genevisible; Q92574; HS.
DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR GO; GO:0101031; C:chaperone complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR GO; GO:0030027; C:lamellipodium; IDA:UniProtKB.
DR GO; GO:0005811; C:lipid droplet; IDA:HPA.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:ParkinsonsUK-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:ParkinsonsUK-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0033596; C:TSC1-TSC2 complex; IDA:UniProtKB.
DR GO; GO:0042030; F:ATPase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; IPI:UniProtKB.
DR GO; GO:0032794; F:GTPase activating protein binding; IEA:Ensembl.
DR GO; GO:0030544; F:Hsp70 protein binding; IDA:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; IPI:UniProtKB.
DR GO; GO:0047485; F:protein N-terminus binding; IPI:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR GO; GO:0090630; P:activation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:Ensembl.
DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL.
DR GO; GO:0008306; P:associative learning; IEA:Ensembl.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0030030; P:cell projection organization; IEA:Ensembl.
DR GO; GO:0007160; P:cell-matrix adhesion; IMP:UniProtKB.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; ISS:ParkinsonsUK-UCL.
DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl.
DR GO; GO:0046323; P:glucose import; IEA:Ensembl.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0043379; P:memory T cell differentiation; IEA:Ensembl.
DR GO; GO:0042552; P:myelination; IEA:Ensembl.
DR GO; GO:0032780; P:negative regulation of ATP-dependent activity; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0045792; P:negative regulation of cell size; IEA:Ensembl.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IEA:Ensembl.
DR GO; GO:0016242; P:negative regulation of macroautophagy; ISS:ParkinsonsUK-UCL.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:1903204; P:negative regulation of oxidative stress-induced neuron death; IEA:Ensembl.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IDA:ComplexPortal.
DR GO; GO:0017148; P:negative regulation of translation; IMP:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IDA:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IEA:Ensembl.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IEA:Ensembl.
DR GO; GO:0006813; P:potassium ion transport; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
DR GO; GO:0001952; P:regulation of cell-matrix adhesion; IMP:UniProtKB.
DR GO; GO:1901214; P:regulation of neuron death; ISS:ParkinsonsUK-UCL.
DR GO; GO:0043666; P:regulation of phosphoprotein phosphatase activity; IMP:UniProtKB.
DR GO; GO:0045859; P:regulation of protein kinase activity; IEA:Ensembl.
DR GO; GO:0051492; P:regulation of stress fiber assembly; IDA:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB.
DR GO; GO:0032868; P:response to insulin; IDA:UniProtKB.
DR GO; GO:0006407; P:rRNA export from nucleus; IMP:UniProtKB.
DR GO; GO:0050808; P:synapse organization; IEA:Ensembl.
DR DisProt; DP02744; -.
DR InterPro; IPR007483; Hamartin.
DR PANTHER; PTHR15154; PTHR15154; 1.
DR Pfam; PF04388; Hamartin; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chaperone; Coiled coil; Cytoplasm;
KW Disease variant; Epilepsy; Membrane; Phosphoprotein; Reference proteome;
KW Tumor suppressor.
FT CHAIN 1..1164
FT /note="Hamartin"
FT /id="PRO_0000065651"
FT REGION 403..787
FT /note="Mediates interaction with WDR45B"
FT /evidence="ECO:0000269|PubMed:28561066"
FT REGION 439..571
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1006..1085
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1131..1164
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 721..997
FT /evidence="ECO:0000255"
FT COMPBIAS 468..484
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 512..534
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1017..1049
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1059..1084
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 487
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 505
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15963462,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 511
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 598
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 1100
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 70..120
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042890"
FT VARIANT 22
FT /note="R -> W (in FCORD2; somatic mutation; decreased
FT interaction with TSC2; decreased function in negative
FT regulation of TOR signaling; dbSNP:rs749030456)"
FT /evidence="ECO:0000269|PubMed:28215400"
FT /id="VAR_078844"
FT VARIANT 51
FT /note="E -> D (in TSC1; unknown pathological significance;
FT dbSNP:rs118203342)"
FT /id="VAR_009397"
FT VARIANT 61
FT /note="L -> R (in TSC1; unknown pathological significance;
FT reduced expression; altered subcellular localization;
FT reduced inhibition of TORC1 signaling; dbSNP:rs118203345)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070636"
FT VARIANT 68
FT /note="H -> R (in a bladder tumor; somatic mutation;
FT reduced stability; does not affect interaction with TSC2;
FT dbSNP:rs118203347)"
FT /evidence="ECO:0000269|PubMed:18397877"
FT /id="VAR_054386"
FT VARIANT 72
FT /note="L -> P (in TSC1; dbSNP:rs118203354)"
FT /evidence="ECO:0000269|PubMed:10533069"
FT /id="VAR_054387"
FT VARIANT 117
FT /note="L -> P (in TSC1; reduced expression; altered
FT subcellular localization; reduced interaction with TSC2;
FT reduced inhibition of TORC1 signaling; dbSNP:rs118203368)"
FT /evidence="ECO:0000269|PubMed:18830229,
FT ECO:0000269|PubMed:22161988, ECO:0000269|PubMed:29127155"
FT /id="VAR_070637"
FT VARIANT 126
FT /note="V -> I (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514843)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070638"
FT VARIANT 128
FT /note="Missing (in TSC1; reduced expression; reduced
FT inhibition of TORC1 signaling)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070639"
FT VARIANT 132
FT /note="G -> D (in TSC1; unknown pathological significance;
FT reduced expression; altered subcellular localization;
FT reduced inhibition of TORC1 signaling; dbSNP:rs397514784)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070640"
FT VARIANT 133
FT /note="V -> I (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs118203381)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070641"
FT VARIANT 158
FT /note="F -> C (in a bladder tumor; somatic mutation;
FT reduced stability; does not affect interaction with TSC2;
FT dbSNP:rs118203385)"
FT /evidence="ECO:0000269|PubMed:18397877"
FT /id="VAR_054388"
FT VARIANT 158
FT /note="F -> S (found in a patient suspected of having
FT tuberous sclerosis; unknown pathological significance;
FT reduced expression; altered subcellular localization;
FT reduced inhibition of TORC1 signaling; dbSNP:rs118203385)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070642"
FT VARIANT 165..1164
FT /note="Missing (in TSC1)"
FT /evidence="ECO:0000269|PubMed:11829138"
FT /id="VAR_078845"
FT VARIANT 180
FT /note="L -> P (in TSC1; reduced expression; reduced
FT inhibition of TORC1 signaling; dbSNP:rs118203396)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070643"
FT VARIANT 190
FT /note="R -> S"
FT /id="VAR_009398"
FT VARIANT 191
FT /note="L -> H (in TSC1; reduced expression; reduced
FT inhibition of TORC1 signaling; dbSNP:rs118203403)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_009399"
FT VARIANT 198..199
FT /note="NF -> I (in TSC1; reduced expression; altered
FT subcellular localization; reduced interaction with TSC2;
FT reduced inhibition of TORC1 signaling)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_009400"
FT VARIANT 204
FT /note="R -> C (in FCORD2; somatic mutation; decreased
FT interaction with TSC2; decreased function in negative
FT regulation of TOR signaling; dbSNP:rs1060505021)"
FT /evidence="ECO:0000269|PubMed:28215400"
FT /id="VAR_078846"
FT VARIANT 204
FT /note="R -> P (found in a patient suspected of having
FT tuberous sclerosis; reduced expression; altered subcellular
FT localization; reduced inhibition of TORC1 signaling;
FT dbSNP:rs397514834)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070644"
FT VARIANT 206
FT /note="H -> D (in a bladder tumor; somatic mutation;
FT reduced stability; does not affect interaction with TSC2)"
FT /evidence="ECO:0000269|PubMed:18397877"
FT /id="VAR_054389"
FT VARIANT 216
FT /note="F -> L (in a bladder tumor; diffuse punctate
FT cytoplasmic distribution in aminoacid-starved conditions;
FT does not affect interaction with TSC2; dbSNP:rs1323541164)"
FT /evidence="ECO:0000269|PubMed:18397877"
FT /id="VAR_054390"
FT VARIANT 224
FT /note="M -> R (in TSC1; reduced expression; reduced
FT inhibition of TORC1 signaling; dbSNP:rs118203426)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_009401"
FT VARIANT 246
FT /note="R -> K (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on inhibition of TORC1
FT signaling; dbSNP:rs118203436)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070645"
FT VARIANT 305
FT /note="G -> R (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on inhibition of TORC1
FT signaling; dbSNP:rs118203468)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070646"
FT VARIANT 305
FT /note="G -> W (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on inhibition of TORC1
FT signaling; dbSNP:rs118203468)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070647"
FT VARIANT 322
FT /note="M -> T (in dbSNP:rs1073123)"
FT /evidence="ECO:0000269|PubMed:10533067,
FT ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950,
FT ECO:0000269|PubMed:9328481, ECO:0000269|PubMed:9924605"
FT /id="VAR_009402"
FT VARIANT 336
FT /note="R -> Q (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514808)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070648"
FT VARIANT 362
FT /note="P -> S (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514864)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070649"
FT VARIANT 411
FT /note="L -> I (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514840)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070650"
FT VARIANT 417
FT /note="T -> I (in TSC1; unknown pathological significance;
FT does not affect interaction with TSC2; dbSNP:rs77464996)"
FT /evidence="ECO:0000269|PubMed:10570911,
FT ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:18397877"
FT /id="VAR_009403"
FT VARIANT 448
FT /note="P -> S (no effect on expression; no effect on
FT subcellular localization; no effect on inhibition of TORC1
FT signaling; dbSNP:rs118203518)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070651"
FT VARIANT 500
FT /note="R -> Q (in TSC1; dbSNP:rs118203538)"
FT /evidence="ECO:0000269|PubMed:10874311"
FT /id="VAR_054391"
FT VARIANT 509
FT /note="R -> Q (no effect on expression; no effect on
FT inhibition of TORC1 signaling; dbSNP:rs118203543)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070652"
FT VARIANT 523
FT /note="A -> P (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs118203548)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070653"
FT VARIANT 567
FT /note="A -> V (no effect on expression; no effect on
FT subcellular localization; no effect on inhibition of TORC1
FT signaling; dbSNP:rs397514880)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070654"
FT VARIANT 577
FT /note="E -> D (in dbSNP:rs118203571)"
FT /evidence="ECO:0000269|PubMed:10607950"
FT /id="VAR_009404"
FT VARIANT 586..589
FT /note="CKIP -> S (in TSC1)"
FT /id="VAR_009405"
FT VARIANT 587
FT /note="K -> R (in dbSNP:rs118203576)"
FT /evidence="ECO:0000269|PubMed:9242607,
FT ECO:0000269|PubMed:9924605"
FT /id="VAR_009406"
FT VARIANT 654
FT /note="Q -> E (in TSC1; dbSNP:rs75820036)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009407"
FT VARIANT 693
FT /note="D -> H (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514800)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070655"
FT VARIANT 698
FT /note="L -> R (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514802)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070656"
FT VARIANT 701
FT /note="Q -> H (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs118203639)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070657"
FT VARIANT 726
FT /note="A -> E (in TSC1; dbSNP:rs118203655)"
FT /evidence="ECO:0000269|PubMed:9328481"
FT /id="VAR_009408"
FT VARIANT 732
FT /note="H -> Y (might be associated with susceptibility to
FT focal cortical dysplasia of the Taylor balloon cell type;
FT dbSNP:rs118203657)"
FT /evidence="ECO:0000269|PubMed:10533067,
FT ECO:0000269|PubMed:12112044, ECO:0000269|PubMed:9328481,
FT ECO:0000269|PubMed:9924605"
FT /id="VAR_009409"
FT VARIANT 762
FT /note="N -> S (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs118203670)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070658"
FT VARIANT 809
FT /note="E -> Q (in dbSNP:rs118203692)"
FT /evidence="ECO:0000269|PubMed:10533067"
FT /id="VAR_009410"
FT VARIANT 811
FT /note="R -> G (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514814)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070659"
FT VARIANT 829
FT /note="S -> R (in dbSNP:rs118203699)"
FT /evidence="ECO:0000269|PubMed:10607950"
FT /id="VAR_009411"
FT VARIANT 883
FT /note="A -> T (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs118203721)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070660"
FT VARIANT 899
FT /note="T -> S (in TSC1; dbSNP:rs76801599)"
FT /evidence="ECO:0000269|PubMed:10570911"
FT /id="VAR_009412"
FT VARIANT 978
FT /note="L -> V (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514859)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070661"
FT VARIANT 1035
FT /note="G -> S (no effect on expression; no effect on
FT inhibition of TORC1 signaling; dbSNP:rs118203742)"
FT /evidence="ECO:0000269|PubMed:18830229,
FT ECO:0000269|PubMed:9328481, ECO:0000269|PubMed:9924605"
FT /id="VAR_009413"
FT VARIANT 1043
FT /note="Missing (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070662"
FT VARIANT 1097
FT /note="R -> H (no effect on expression; no effect on
FT inhibition of TORC1 signaling; dbSNP:rs118203750)"
FT /evidence="ECO:0000269|PubMed:18830229"
FT /id="VAR_070663"
FT VARIANT 1108
FT /note="G -> S (in dbSNP:rs118203753)"
FT /evidence="ECO:0000269|PubMed:9924605"
FT /id="VAR_009414"
FT VARIANT 1146
FT /note="D -> Y (in TSC1; unknown pathological significance;
FT no effect on expression; no effect on subcellular
FT localization; no effect on inhibition of TORC1 signaling;
FT dbSNP:rs397514806)"
FT /evidence="ECO:0000269|PubMed:22161988"
FT /id="VAR_070664"
FT HELIX 941..971
FT /evidence="ECO:0007829|PDB:4Z6Y"
FT HELIX 975..991
FT /evidence="ECO:0007829|PDB:4Z6Y"
SQ SEQUENCE 1164 AA; 129767 MW; EF15509385C7AACC CRC64;
MAQQANVGEL LAMLDSPMLG VRDDVTAVFK ENLNSDRGPM LVNTLVDYYL ETSSQPALHI
LTTLQEPHDK HLLDRINEYV GKAATRLSIL SLLGHVIRLQ PSWKHKLSQA PLLPSLLKCL
KMDTDVVVLT TGVLVLITML PMIPQSGKQH LLDFFDIFGR LSSWCLKKPG HVAEVYLVHL
HASVYALFHR LYGMYPCNFV SFLRSHYSMK ENLETFEEVV KPMMEHVRIH PELVTGSKDH
ELDPRRWKRL ETHDVVIECA KISLDPTEAS YEDGYSVSHQ ISARFPHRSA DVTTSPYADT
QNSYGCATST PYSTSRLMLL NMPGQLPQTL SSPSTRLITE PPQATLWSPS MVCGMTTPPT
SPGNVPPDLS HPYSKVFGTT AGGKGTPLGT PATSPPPAPL CHSDDYVHIS LPQATVTPPR
KEERMDSARP CLHRQHHLLN DRGSEEPPGS KGSVTLSDLP GFLGDLASEE DSIEKDKEEA
AISRELSEIT TAEAEPVVPR GGFDSPFYRD SLPGSQRKTH SAASSSQGAS VNPEPLHSSL
DKLGPDTPKQ AFTPIDLPCG SADESPAGDR ECQTSLETSI FTPSPCKIPP PTRVGFGSGQ
PPPYDHLFEV ALPKTAHHFV IRKTEELLKK AKGNTEEDGV PSTSPMEVLD RLIQQGADAH
SKELNKLPLP SKSVDWTHFG GSPPSDEIRT LRDQLLLLHN QLLYERFKRQ QHALRNRRLL
RKVIKAAALE EHNAAMKDQL KLQEKDIQMW KVSLQKEQAR YNQLQEQRDT MVTKLHSQIR
QLQHDREEFY NQSQELQTKL EDCRNMIAEL RIELKKANNK VCHTELLLSQ VSQKLSNSES
VQQQMEFLNR QLLVLGEVNE LYLEQLQNKH SDTTKEVEMM KAAYRKELEK NRSHVLQQTQ
RLDTSQKRIL ELESHLAKKD HLLLEQKKYL EDVKLQARGQ LQAAESRYEA QKRITQVFEL
EILDLYGRLE KDGLLKKLEE EKAEAAEAAE ERLDCCNDGC SDSMVGHNEE ASGHNGETKT
PRPSSARGSS GSRGGGGSSS SSSELSTPEK PPHQRAGPFS SRWETTMGEA SASIPTTVGS
LPSSKSFLGM KARELFRNKS ESQCDEDGMT SSLSESLKTE LGKDLGVEAK IPLNLDGPHP
SPPTPDSVGQ LHIMDYNETH HEHS
