TBCD4_HUMAN
ID TBCD4_HUMAN Reviewed; 1298 AA.
AC O60343; A7E2X8; B4DU25; B4E235; B6ETN8; B6ETN9; Q5W0B9; Q68D14;
DT 10-OCT-2002, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2005, sequence version 2.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=TBC1 domain family member 4;
DE AltName: Full=Akt substrate of 160 kDa;
DE Short=AS160;
GN Name=TBC1D4; Synonyms=AS160, KIAA0603;
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] (ISOFORMS 2 AND 3), FUNCTION, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION AT THR-642.
RC TISSUE=Testis;
RX PubMed=18771725; DOI=10.1016/j.cellsig.2008.08.010;
RA Baus D., Heermeier K., De Hoop M., Metz-Weidmann C., Gassenhuber J.,
RA Dittrich W., Welte S., Tennagels N.;
RT "Identification of a novel AS160 splice variant that regulates GLUT4
RT translocation and glucose-uptake in rat muscle cells.";
RL Cell. Signal. 20:2237-2246(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ILE-819 AND ALA-1275.
RC TISSUE=Brain;
RX PubMed=19077034; DOI=10.1111/j.1365-2443.2008.01251.x;
RA Ishibashi K., Kanno E., Itoh T., Fukuda M.;
RT "Identification and characterization of a novel Tre-2/Bub2/Cdc16 (TBC)
RT protein that possesses Rab3A-GAP activity.";
RL Genes Cells 14:41-52(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS ILE-819
RP AND ALA-1275.
RC TISSUE=Brain;
RX PubMed=9628581; DOI=10.1093/dnares/5.1.31;
RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N.,
RA Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. IX. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 5:31-39(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5).
RC TISSUE=Placenta, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS ILE-819
RP AND ALA-1275.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 600-1298 (ISOFORM 3), AND VARIANT
RP ILE-819.
RC TISSUE=Fetal liver;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP PHOSPHORYLATION AT SER-588 AND THR-642.
RX PubMed=11994271; DOI=10.1074/jbc.c200198200;
RA Kane S., Sano H., Liu S.C.H., Asara J.M., Lane W.S., Garner C.C.,
RA Lienhard G.E.;
RT "A method to identify serine kinase substrates. Akt phosphorylates a novel
RT adipocyte protein with a Rab GTPase-activating protein (GAP) domain.";
RL J. Biol. Chem. 277:22115-22118(2002).
RN [9]
RP MUTAGENESIS OF SER-318; SER-588; THR-642; SER-751 AND ARG-972, AND EFFECT
RP ON GLUT4 TRANSLOCATION.
RX PubMed=12637568; DOI=10.1074/jbc.c300063200;
RA Sano H., Kane S., Sano E., Miinea C.P., Asara J.M., Lane W.S., Garner C.W.,
RA Lienhard G.E.;
RT "Insulin-stimulated phosphorylation of a Rab GTPase-activating protein
RT regulates GLUT4 translocation.";
RL J. Biol. Chem. 278:14599-14602(2003).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF ARG-972.
RX PubMed=15971998; DOI=10.1042/bj20050887;
RA Miinea C.P., Sano H., Kane S., Sano E., Fukuda M., Peraenen J., Lane W.S.,
RA Lienhard G.E.;
RT "AS160, the Akt substrate regulating GLUT4 translocation, has a functional
RT Rab GTPase-activating protein domain.";
RL Biochem. J. 391:87-93(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-344, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-588 AND SER-591, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [13]
RP TISSUE SPECIFICITY.
RX PubMed=18276765; DOI=10.2337/db07-1469;
RA Bouzakri K., Ribaux P., Tomas A., Parnaud G., Rickenbach K., Halban P.A.;
RT "Rab GTPase-activating protein AS160 is a major downstream effector of
RT protein kinase B/Akt signaling in pancreatic beta-cells.";
RL Diabetes 57:1195-1204(2008).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=15304337; DOI=10.1016/j.febslet.2004.07.023;
RA Matsumoto Y., Imai Y., Lu Yoshida N., Sugita Y., Tanaka T., Tsujimoto G.,
RA Saito H., Oshida T.;
RT "Upregulation of the transcript level of GTPase activating protein KIAA0603
RT in T cells from patients with atopic dermatitis.";
RL FEBS Lett. 572:135-140(2004).
RN [15]
RP PHOSPHORYLATION.
RX PubMed=15919790; DOI=10.2337/diabetes.54.6.1692;
RA Karlsson H.K.R., Zierath J.R., Kane S., Krook A., Lienhard G.E.,
RA Wallberg-Henriksson H.;
RT "Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired
RT in skeletal muscle of type 2 diabetic subjects.";
RL Diabetes 54:1692-1697(2005).
RN [16]
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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-341; SER-566 AND SER-570,
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-666; SER-672 AND SER-678
RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP 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 [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP 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 [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-566; THR-568; SER-570 AND
RP SER-588, 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 [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-477, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-341; SER-566 AND SER-588,
RP VARIANT [LARGE SCALE ANALYSIS] ILE-819, AND IDENTIFICATION BY MASS
RP 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 [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-341; SER-344; SER-588 AND
RP SER-591, AND IDENTIFICATION BY 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 [24]
RP FUNCTION.
RX PubMed=22908308; DOI=10.1083/jcb.201111091;
RA Chen Y., Wang Y., Zhang J., Deng Y., Jiang L., Song E., Wu X.S.,
RA Hammer J.A., Xu T., Lippincott-Schwartz J.;
RT "Rab10 and myosin-Va mediate insulin-stimulated GLUT4 storage vesicle
RT translocation in adipocytes.";
RL J. Cell Biol. 198:545-560(2012).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-314; SER-341; SER-566;
RP THR-568; SER-570; SER-588; SER-591; SER-666 AND SER-754, AND IDENTIFICATION
RP 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 [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-262; SER-588 AND SER-591, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [27]
RP INVOLVEMENT IN NIDDM5.
RX PubMed=25043022; DOI=10.1038/nature13425;
RA Moltke I., Grarup N., Jorgensen M.E., Bjerregaard P., Treebak J.T.,
RA Fumagalli M., Korneliussen T.S., Andersen M.A., Nielsen T.S., Krarup N.T.,
RA Gjesing A.P., Zierath J.R., Linneberg A., Wu X., Sun G., Jin X.,
RA Al-Aama J., Wang J., Borch-Johnsen K., Pedersen O., Nielsen R.,
RA Albrechtsen A., Hansen T.;
RT "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and
RT type 2 diabetes.";
RL Nature 512:190-193(2014).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 874-1170.
RX PubMed=21454505; DOI=10.1074/jbc.m110.217323;
RA Park S.Y., Jin W., Woo J.R., Shoelson S.E.;
RT "Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating
RT protein (RabGAP) domains reveal critical elements for GLUT4
RT translocation.";
RL J. Biol. Chem. 286:18130-18138(2011).
CC -!- FUNCTION: May act as a GTPase-activating protein for RAB2A, RAB8A,
CC RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter
CC SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing
CC glucose uptake. {ECO:0000269|PubMed:15971998,
CC ECO:0000269|PubMed:18771725, ECO:0000269|PubMed:22908308}.
CC -!- INTERACTION:
CC O60343; P63104: YWHAZ; NbExp=2; IntAct=EBI-522028, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18771725}.
CC Note=Isoform 2 shows a cytoplasmic perinuclear localization in a
CC myoblastic cell line in resting and insulin-stimulated cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=O60343-1; Sequence=Displayed;
CC Name=2; Synonyms=AS160_tv2;
CC IsoId=O60343-2; Sequence=VSP_036869;
CC Name=3; Synonyms=AS160_tv3;
CC IsoId=O60343-3; Sequence=VSP_036870;
CC Name=4;
CC IsoId=O60343-4; Sequence=VSP_036868, VSP_036871;
CC Name=5;
CC IsoId=O60343-5; Sequence=VSP_036868;
CC -!- TISSUE SPECIFICITY: Widely expressed. Isoform 2 is the highest
CC overexpressed in most tissues. Isoform 1 is highly expressed in
CC skeletal muscle and heart, but was not detectable in the liver nor in
CC adipose tissue. Isoform 2 is strongly expressed in adrenal and thyroid
CC gland, and also in lung, kidney, colon, brain and adipose tissue.
CC Isoform 2 is moderately expressed in skeletal muscle. Expressed in
CC pancreatic Langerhans islets, including beta cells (at protein level).
CC Expression is decreased by twofold in pancreatic islets in type 2
CC diabetes patients compared to control subjects. Up-regulated in T-cells
CC from patients with atopic dermatitis. {ECO:0000269|PubMed:15304337,
CC ECO:0000269|PubMed:18276765, ECO:0000269|PubMed:18771725}.
CC -!- PTM: Phosphorylated by AKT1; insulin-induced. Also phosphorylated by
CC AMPK in response to insulin. Insulin-stimulated phosphorylation is
CC required for SLC2A4/GLUT4 translocation. Has no effect on SLC2A4/GLUT4
CC internalization. Physiological hyperinsulinemia increases
CC phosphorylation in skeletal muscle. Insulin-stimulated phosphorylation
CC is reduced by 39% in type 2 diabetic patients.
CC {ECO:0000269|PubMed:11994271, ECO:0000269|PubMed:15919790,
CC ECO:0000269|PubMed:18771725}.
CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent, 5 (NIDDM5)
CC [MIM:616087]: A multifactorial disorder of glucose homeostasis caused
CC by a lack of sensitivity to the body's own insulin. Affected
CC individuals usually have an obese body habitus and manifestations of a
CC metabolic syndrome characterized by diabetes, insulin resistance,
CC hypertension and hypertriglyceridemia. The disease results in long-term
CC complications that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000269|PubMed:25043022}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA25529.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; FM207106; CAR62509.1; -; mRNA.
DR EMBL; FM207107; CAR62510.1; -; mRNA.
DR EMBL; AB449885; BAH16628.1; -; mRNA.
DR EMBL; AB011175; BAA25529.2; ALT_INIT; mRNA.
DR EMBL; AK300468; BAG62187.1; -; mRNA.
DR EMBL; AK304091; BAG64997.1; -; mRNA.
DR EMBL; AL139230; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL162571; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC151239; AAI51240.1; -; mRNA.
DR EMBL; CR749622; CAH18416.1; -; mRNA.
DR CCDS; CCDS41901.1; -. [O60343-1]
DR CCDS; CCDS66563.1; -. [O60343-2]
DR CCDS; CCDS66564.1; -. [O60343-3]
DR PIR; T00261; T00261.
DR RefSeq; NP_001273587.1; NM_001286658.2. [O60343-3]
DR RefSeq; NP_001273588.1; NM_001286659.2. [O60343-2]
DR RefSeq; NP_055647.2; NM_014832.4. [O60343-1]
DR PDB; 3QYB; X-ray; 3.50 A; A=874-1170.
DR PDB; 7NIX; X-ray; 1.90 A; B=637-647.
DR PDBsum; 3QYB; -.
DR PDBsum; 7NIX; -.
DR AlphaFoldDB; O60343; -.
DR SMR; O60343; -.
DR BioGRID; 115213; 126.
DR IntAct; O60343; 55.
DR MINT; O60343; -.
DR STRING; 9606.ENSP00000366863; -.
DR TCDB; 8.A.87.1.1; the tbc1 domain (tbc1) family.
DR GlyGen; O60343; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O60343; -.
DR MetOSite; O60343; -.
DR PhosphoSitePlus; O60343; -.
DR BioMuta; TBC1D4; -.
DR EPD; O60343; -.
DR jPOST; O60343; -.
DR MassIVE; O60343; -.
DR MaxQB; O60343; -.
DR PaxDb; O60343; -.
DR PeptideAtlas; O60343; -.
DR PRIDE; O60343; -.
DR ProteomicsDB; 49366; -. [O60343-1]
DR ProteomicsDB; 49367; -. [O60343-2]
DR ProteomicsDB; 49368; -. [O60343-3]
DR ProteomicsDB; 49369; -. [O60343-4]
DR ProteomicsDB; 49370; -. [O60343-5]
DR Antibodypedia; 3177; 502 antibodies from 40 providers.
DR DNASU; 9882; -.
DR Ensembl; ENST00000377625.6; ENSP00000366852.2; ENSG00000136111.14. [O60343-2]
DR Ensembl; ENST00000377636.8; ENSP00000366863.3; ENSG00000136111.14. [O60343-1]
DR Ensembl; ENST00000431480.6; ENSP00000395986.2; ENSG00000136111.14. [O60343-3]
DR GeneID; 9882; -.
DR KEGG; hsa:9882; -.
DR MANE-Select; ENST00000377636.8; ENSP00000366863.3; NM_014832.5; NP_055647.2.
DR UCSC; uc001vjl.3; human. [O60343-1]
DR CTD; 9882; -.
DR DisGeNET; 9882; -.
DR GeneCards; TBC1D4; -.
DR HGNC; HGNC:19165; TBC1D4.
DR HPA; ENSG00000136111; Tissue enhanced (skeletal).
DR MalaCards; TBC1D4; -.
DR MIM; 612465; gene.
DR MIM; 616087; phenotype.
DR neXtProt; NX_O60343; -.
DR OpenTargets; ENSG00000136111; -.
DR PharmGKB; PA38807; -.
DR VEuPathDB; HostDB:ENSG00000136111; -.
DR eggNOG; KOG4436; Eukaryota.
DR GeneTree; ENSGT00940000158486; -.
DR HOGENOM; CLU_005350_13_2_1; -.
DR InParanoid; O60343; -.
DR OMA; PCDEGEP; -.
DR OrthoDB; 323342at2759; -.
DR PhylomeDB; O60343; -.
DR TreeFam; TF317184; -.
DR PathwayCommons; O60343; -.
DR Reactome; R-HSA-1445148; Translocation of SLC2A4 (GLUT4) to the plasma membrane.
DR SignaLink; O60343; -.
DR SIGNOR; O60343; -.
DR BioGRID-ORCS; 9882; 9 hits in 1076 CRISPR screens.
DR ChiTaRS; TBC1D4; human.
DR EvolutionaryTrace; O60343; -.
DR GeneWiki; TBC1D4; -.
DR GenomeRNAi; 9882; -.
DR Pharos; O60343; Tbio.
DR PRO; PR:O60343; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; O60343; protein.
DR Bgee; ENSG00000136111; Expressed in skeletal muscle tissue of rectus abdominis and 206 other tissues.
DR ExpressionAtlas; O60343; baseline and differential.
DR Genevisible; O60343; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0031982; C:vesicle; IEA:Ensembl.
DR GO; GO:0005096; F:GTPase activator activity; IBA:GO_Central.
DR GO; GO:0090630; P:activation of GTPase activity; IBA:GO_Central.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:UniProtKB.
DR GO; GO:0031339; P:negative regulation of vesicle fusion; IEA:Ensembl.
DR GO; GO:0016192; P:vesicle-mediated transport; IMP:UniProtKB.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR021785; DUF3350.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006020; PTB/PI_dom.
DR InterPro; IPR000195; Rab-GTPase-TBC_dom.
DR InterPro; IPR035969; Rab-GTPase_TBC_sf.
DR Pfam; PF11830; DUF3350; 1.
DR Pfam; PF00640; PID; 2.
DR Pfam; PF00566; RabGAP-TBC; 1.
DR SMART; SM00462; PTB; 2.
DR SMART; SM00164; TBC; 1.
DR SUPFAM; SSF47923; SSF47923; 2.
DR PROSITE; PS01179; PID; 1.
DR PROSITE; PS50086; TBC_RABGAP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW Diabetes mellitus; GTPase activation; Methylation; Phosphoprotein;
KW Reference proteome; Repeat.
FT CHAIN 1..1298
FT /note="TBC1 domain family member 4"
FT /id="PRO_0000208026"
FT DOMAIN 53..209
FT /note="PID 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT DOMAIN 312..468
FT /note="PID 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT DOMAIN 918..1112
FT /note="Rab-GAP TBC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00163"
FT REGION 1..31
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 241..287
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 317..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 586..685
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 725..765
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..25
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 666..685
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 747..765
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 262
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 314
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 318
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 341
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 344
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:21406692"
FT MOD_RES 477
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 566
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 568
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 570
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 577
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 588
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:11994271,
FT ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 591
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 609
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 613
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 617
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 642
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000269|PubMed:11994271,
FT ECO:0000269|PubMed:18771725"
FT MOD_RES 666
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 751
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 754
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 757
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT MOD_RES 763
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8BYJ6"
FT VAR_SEQ 1..783
FT /note="Missing (in isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_036868"
FT VAR_SEQ 678..740
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:18771725"
FT /id="VSP_036869"
FT VAR_SEQ 733..740
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005,
FT ECO:0000303|PubMed:18771725"
FT /id="VSP_036870"
FT VAR_SEQ 865..917
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_036871"
FT VARIANT 619
FT /note="P -> L (in dbSNP:rs56223054)"
FT /id="VAR_061891"
FT VARIANT 819
FT /note="V -> I (in dbSNP:rs1062087)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:19077034,
FT ECO:0000269|PubMed:9628581, ECO:0007744|PubMed:20068231"
FT /id="VAR_059855"
FT VARIANT 1119
FT /note="V -> A (in dbSNP:rs58232698)"
FT /id="VAR_061892"
FT VARIANT 1147
FT /note="T -> M (in dbSNP:rs9600455)"
FT /id="VAR_052534"
FT VARIANT 1275
FT /note="V -> A (in dbSNP:rs557337)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:19077034, ECO:0000269|PubMed:9628581"
FT /id="VAR_052535"
FT VARIANT 1284
FT /note="L -> I (in dbSNP:rs11616741)"
FT /id="VAR_054862"
FT MUTAGEN 318
FT /note="S->A: 80% reduction of insulin-stimulated GLUT4
FT translocation; when associated with A-588; A-642 and A-
FT 751."
FT /evidence="ECO:0000269|PubMed:12637568"
FT MUTAGEN 588
FT /note="S->A: 80% reduction of insulin-stimulated GLUT4
FT translocation; when associated with A-318; A-642 and A-
FT 751."
FT /evidence="ECO:0000269|PubMed:12637568"
FT MUTAGEN 642
FT /note="T->A: 80% reduction of insulin-stimulated GLUT4
FT translocation; when associated with A-318; A-588 and A-
FT 751."
FT /evidence="ECO:0000269|PubMed:12637568"
FT MUTAGEN 751
FT /note="S->A: 80% reduction of insulin-stimulated GLUT4
FT translocation; when associated with A-318; A-588 and A-
FT 642."
FT /evidence="ECO:0000269|PubMed:12637568"
FT MUTAGEN 972
FT /note="R->K: Loss of Rab GTPase activation. Only 20%
FT reduction of GLUT4 translocation; even when associated with
FT A-318; A-588; A-642 and A-751."
FT /evidence="ECO:0000269|PubMed:12637568,
FT ECO:0000269|PubMed:15971998"
FT CONFLICT 644
FT /note="S -> G (in Ref. 7; CAH18416)"
FT /evidence="ECO:0000305"
FT CONFLICT 845
FT /note="K -> E (in Ref. 7; CAH18416)"
FT /evidence="ECO:0000305"
FT CONFLICT 864
FT /note="E -> EG (in Ref. 2; BAH16628, 3; BAA25529 and 6;
FT AAI51240)"
FT /evidence="ECO:0000305"
FT CONFLICT 867
FT /note="R -> G (in Ref. 7; CAH18416)"
FT /evidence="ECO:0000305"
FT CONFLICT 1137
FT /note="F -> L (in Ref. 7; CAH18416)"
FT /evidence="ECO:0000305"
FT CONFLICT 1178
FT /note="E -> G (in Ref. 4; BAG62187)"
FT /evidence="ECO:0000305"
FT TURN 874..877
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 887..896
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 908..917
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 921..923
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 924..937
FT /evidence="ECO:0007829|PDB:3QYB"
FT STRAND 943..946
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 952..956
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 963..970
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 978..981
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 986..1001
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1002..1005
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1011..1019
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1024..1035
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1036..1039
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1041..1044
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1049..1063
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1067..1075
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1080..1083
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1085..1090
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1091..1095
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1098..1108
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1109..1111
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1115..1124
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1128..1133
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1137..1144
FT /evidence="ECO:0007829|PDB:3QYB"
FT TURN 1145..1149
FT /evidence="ECO:0007829|PDB:3QYB"
FT HELIX 1153..1164
FT /evidence="ECO:0007829|PDB:3QYB"
FT MOD_RES O60343-2:666
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES O60343-2:672
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES O60343-2:678
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
SQ SEQUENCE 1298 AA; 146563 MW; 8DC70CE887C0B311 CRC64;
MEPPSCIQDE PFPHPLEPEP GVSAQPGPGK PSDKRFRLWY VGGSCLDHRT TLPMLPWLMA
EIRRRSQKPE AGGCGAPAAR EVILVLSAPF LRCVPAPGAG ASGGTSPSAT QPNPAVFIFE
HKAQHISRFI HNSHDLTYFA YLIKAQPDDP ESQMACHVFR ATDPSQVPDV ISSIRQLSKA
AMKEDAKPSK DNEDAFYNSQ KFEVLYCGKV TVTHKKAPSS LIDDCMEKFS LHEQQRLKIQ
GEQRGPDPGE DLADLEVVVP GSPGDCLPEE ADGTDTHLGL PAGASQPALT SSRVCFPERI
LEDSGFDEQQ EFRSRCSSVT GVQRRVHEGS QKSQPRRRHA SAPSHVQPSD SEKNRTMLFQ
VGRFEINLIS PDTKSVVLEK NFKDISSCSQ GIKHVDHFGF ICRESPEPGL SQYICYVFQC
ASESLVDEVM LTLKQAFSTA AALQSAKTQI KLCEACPMHS LHKLCERIEG LYPPRAKLVI
QRHLSSLTDN EQADIFERVQ KMKPVSDQEE NELVILHLRQ LCEAKQKTHV HIGEGPSTIS
NSTIPENATS SGRFKLDILK NKAKRSLTSS LENIFSRGAN RMRGRLGSVD SFERSNSLAS
EKDYSPGDSP PGTPPASPPS SAWQTFPEED SDSPQFRRRA HTFSHPPSST KRKLNLQDGR
AQGVRSPLLR QSSSEQCSNL SSVRRMYKES NSSSSLPSLH TSFSAPSFTA PSFLKSFYQN
SGRLSPQYEN EIRQDTASES SDGEGRKRTS STCSNESLSV GGTSVTPRRI SWRQRIFLRV
ASPMNKSPSA MQQQDGLDRN ELLPLSPLSP TMEEEPLVVF LSGEDDPEKI EERKKSKELR
SLWRKAIHQQ ILLLRMEKEN QKLEASRDEL QSRKVKLDYE EVGACQKEVL ITWDKKLLNC
RAKIRCDMED IHTLLKEGVP KSRRGEIWQF LALQYRLRHR LPNKQQPPDI SYKELLKQLT
AQQHAILVDL GRTFPTHPYF SVQLGPGQLS LFNLLKAYSL LDKEVGYCQG ISFVAGVLLL
HMSEEQAFEM LKFLMYDLGF RKQYRPDMMS LQIQMYQLSR LLHDYHRDLY NHLEENEISP
SLYAAPWFLT LFASQFSLGF VARVFDIIFL QGTEVIFKVA LSLLSSQETL IMECESFENI
VEFLKNTLPD MNTSEMEKII TQVFEMDISK QLHAYEVEYH VLQDELQESS YSCEDSETLE
KLERANSQLK RQNMDLLEKL QVAHTKIQAL ESNLENLLTR ETKMKSLIRT LEQEKMAYQK
TVEQLRKLLP ADALVNCDLL LRDLNCNPNN KAKIGNKP
