Full text data of VAC14
VAC14
(TAX1BP2, TRX)
[Confidence: low (only semi-automatic identification from reviews)]
Protein VAC14 homolog (Tax1-binding protein 2)
Protein VAC14 homolog (Tax1-binding protein 2)
UniProt
Q08AM6
ID VAC14_HUMAN Reviewed; 782 AA.
AC Q08AM6; B3KPJ5; Q13174; Q6IA12; Q7L4Y1; Q9BW96; Q9H6V6;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-OCT-2006, sequence version 1.
DT 22-JAN-2014, entry version 70.
DE RecName: Full=Protein VAC14 homolog;
DE AltName: Full=Tax1-binding protein 2;
GN Name=VAC14; Synonyms=TAX1BP2, TRX;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-366, TISSUE SPECIFICITY, AND
RP INTERACTION WITH HTLV-I TAX.
RX PubMed=8611628; DOI=10.1016/0167-4781(96)00012-7;
RA Mireskandari A., Reid R.L., Kashanchi F., Dittmer J., Li W.B.,
RA Brady J.N.;
RT "Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic
RT virus type-I Tax1 binding protein.";
RL Biochim. Biophys. Acta 1306:9-13(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 259-782.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15542851; DOI=10.1128/MCB.24.23.10437-10447.2004;
RA Sbrissa D., Ikonomov O.C., Strakova J., Dondapati R., Mlak K.,
RA Deeb R., Silver R., Shisheva A.;
RT "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that
RT associates with and up-regulates PIKfyve phosphoinositide 5-kinase
RT activity.";
RL Mol. Cell. Biol. 24:10437-10447(2004).
RN [6]
RP INTERACTION WITH NOS1, AND MUTAGENESIS OF GLY-773; ASP-774; LEU-776;
RP ASP-777; 780-VAL--LEU-782 AND LEU-782.
RX PubMed=17161399; DOI=10.1016/j.febslet.2006.11.061;
RA Lemaire J.F., McPherson P.S.;
RT "Binding of Vac14 to neuronal nitric oxide synthase: Characterisation
RT of a new internal PDZ-recognition motif.";
RL FEBS Lett. 580:6948-6954(2006).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE PI(3,5)P2
RP REGULATORY COMPLEX.
RX PubMed=17556371; DOI=10.1074/jbc.M611678200;
RA Sbrissa D., Ikonomov O.C., Fu Z., Ijuin T., Gruenberg J., Takenawa T.,
RA Shisheva A.;
RT "Core protein machinery for mammalian phosphatidylinositol 3,5-
RT bisphosphate synthesis and turnover that regulates the progression of
RT endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve
RT complex.";
RL J. Biol. Chem. 282:23878-23891(2007).
RN [8]
RP SUBUNIT, IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX, AND
RP DOMAIN.
RX PubMed=18950639; DOI=10.1016/j.jmb.2008.10.009;
RA Sbrissa D., Ikonomov O.C., Fenner H., Shisheva A.;
RT "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and
RT Sac3 in a complex to promote PIKfyve activity and functionality.";
RL J. Mol. Biol. 384:766-779(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-11 AND THR-499, AND MASS
RP SPECTROMETRY.
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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
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 [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
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.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: The PI(3,5)P2 regulatory complex regulates both the
CC synthesis and turnover of phosphatidylinositol 3,5-bisphosphate
CC (PtdIns(3,5)P2). Acts as a positive activator of PIKfyve kinase
CC activity. Also required to maintain normal levels of
CC phosphatidylinositol 3-phosphate (PtdIns(3)P) and
CC phosphatidylinositol 5-phosphate (PtdIns(5)P). Plays a role in the
CC biogenesis of endosome carrier vesicles (ECV) / multivesicular
CC bodies (MVB) transport intermediates from early endosomes.
CC -!- SUBUNIT: Forms homooligomers. Component of the PI(3,5)P2
CC regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4
CC and VAC14. VAC14 nucleates the assembly of the complex and serves
CC as a scaffold. Interacts with NOS1. Interacts with HTLV-1 Tax.
CC -!- INTERACTION:
CC P29475:NOS1; NbExp=5; IntAct=EBI-2107455, EBI-7164065;
CC -!- SUBCELLULAR LOCATION: Endosome membrane. Microsome membrane (By
CC similarity). Note=Mainly associated with membranes of the late
CC endocytic pathway.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The C-terminal domain (residues 523-782) mediates
CC homomeric interactions and is necessary for the formation and
CC maintenance of the PI(3,5)P2 regulatory complex.
CC -!- SIMILARITY: Belongs to the VAC14 family.
CC -!- SIMILARITY: Contains 6 HEAT repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB03813.1; Type=Miscellaneous discrepancy; Note=Unknown C-terminal region;
CC Sequence=BAB15145.1; Type=Erroneous initiation;
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DR EMBL; AK025479; BAB15145.1; ALT_INIT; mRNA.
DR EMBL; AK056433; BAG51707.1; -; mRNA.
DR EMBL; BC000536; AAH00536.2; -; mRNA.
DR EMBL; BC007214; AAH07214.2; -; mRNA.
DR EMBL; BC125108; AAI25109.1; -; mRNA.
DR EMBL; BC125109; AAI25110.1; -; mRNA.
DR EMBL; U25801; AAB03813.1; ALT_SEQ; mRNA.
DR EMBL; CR457343; CAG33624.1; -; mRNA.
DR PIR; S68091; S68091.
DR RefSeq; NP_060522.3; NM_018052.3.
DR UniGene; Hs.445061; -.
DR ProteinModelPortal; Q08AM6; -.
DR SMR; Q08AM6; 414-471.
DR IntAct; Q08AM6; 5.
DR MINT; MINT-3997917; -.
DR STRING; 9606.ENSP00000261776; -.
DR PhosphoSite; Q08AM6; -.
DR DMDM; 121940040; -.
DR PaxDb; Q08AM6; -.
DR PRIDE; Q08AM6; -.
DR Ensembl; ENST00000261776; ENSP00000261776; ENSG00000103043.
DR GeneID; 55697; -.
DR KEGG; hsa:55697; -.
DR UCSC; uc002ezm.3; human.
DR CTD; 55697; -.
DR GeneCards; GC16M070721; -.
DR HGNC; HGNC:25507; VAC14.
DR HPA; HPA027766; -.
DR MIM; 604632; gene.
DR neXtProt; NX_Q08AM6; -.
DR PharmGKB; PA142670633; -.
DR eggNOG; NOG287585; -.
DR HOVERGEN; HBG104397; -.
DR InParanoid; Q08AM6; -.
DR KO; K15305; -.
DR OMA; FKCLYGL; -.
DR OrthoDB; EOG7QNVM5; -.
DR PhylomeDB; Q08AM6; -.
DR BioCyc; MetaCyc:ENSG00000103043-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_112621; Metabolism.
DR ChiTaRS; VAC14; human.
DR GeneWiki; VAC14; -.
DR GenomeRNAi; 55697; -.
DR NextBio; 60525; -.
DR PRO; PR:Q08AM6; -.
DR ArrayExpress; Q08AM6; -.
DR Bgee; Q08AM6; -.
DR CleanEx; HS_VAC14; -.
DR Genevestigator; Q08AM6; -.
DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-KW.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0031902; C:late endosome membrane; TAS:Reactome.
DR GO; GO:0019209; F:kinase activator activity; IEA:InterPro.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.25.10.10; -; 2.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR026825; VAC14.
DR InterPro; IPR021841; VAC14_Fig4p-bd.
DR PANTHER; PTHR16023; PTHR16023; 1.
DR Pfam; PF11916; Vac14_Fig4_bd; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR PROSITE; PS50077; HEAT_REPEAT; FALSE_NEG.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Endoplasmic reticulum; Endosome;
KW Host-virus interaction; Membrane; Microsome; Phosphoprotein;
KW Reference proteome; Repeat.
FT CHAIN 1 782 Protein VAC14 homolog.
FT /FTId=PRO_0000300485.
FT REPEAT 5 42 HEAT 1.
FT REPEAT 89 126 HEAT 2.
FT REPEAT 171 208 HEAT 3.
FT REPEAT 212 249 HEAT 4.
FT REPEAT 438 475 HEAT 5.
FT REPEAT 560 598 HEAT 6.
FT REGION 773 777 Mediates interaction with the PDZ domain
FT of NOS1.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 11 11 Phosphothreonine.
FT MOD_RES 499 499 Phosphothreonine.
FT MUTAGEN 773 773 G->A: Reduces interaction with NOS1.
FT MUTAGEN 774 774 D->A: Reduces interaction with NOS1.
FT MUTAGEN 776 776 L->A: Reduces interaction with NOS1.
FT MUTAGEN 777 777 D->A: Abolishes interaction with NOS1.
FT MUTAGEN 780 782 VVL->AAA: Reduces interaction with NOS1.
FT MUTAGEN 782 782 L->G: Reduces interaction with NOS1.
FT CONFLICT 257 257 A -> P (in Ref. 3; AAB03813).
FT CONFLICT 263 263 L -> P (in Ref. 3; AAB03813).
FT CONFLICT 352 352 T -> A (in Ref. 4; CAG33624).
SQ SEQUENCE 782 AA; 87973 MW; B39AC1F4D619570F CRC64;
MNPEKDFAPL TPNIVRALND KLYEKRKVAA LEIEKLVREF VAQNNTVQIK HVIQTLSQEF
ALSQHPHSRK GGLIGLAACS IALGKDSGLY LKELIEPVLT CFNDADSRLR YYACEALYNI
VKVARGAVLP HFNVLFDGLS KLAADPDPNV KSGSELLDRL LKDIVTESNK FDLVSFIPLL
RERIYSNNQY ARQFIISWIL VLESVPDINL LDYLPEILDG LFQILGDNGK EIRKMCEVVL
GEFLKEIKKN PSSVKFAEMA NILVIHCQTT DDLIQLTAMC WMREFIQLAG RVMLPYSSGI
LTAVLPCLAY DDRKKSIKEV ANVCNQSLMK LVTPEDDELD ELRPGQRQAE PTPDDALPKQ
EGTASGGPDG SCDSSFSSGI SVFTAASTER APVTLHLDGI VQVLNCHLSD TAIGMMTRIA
VLKWLYHLYI KTPRKMFRHT DSLFPILLQT LSDESDEVIL KDLEVLAEIA SSPAGQTDDP
GPLDGPDLQA SHSELQVPTP GRAGLLNTSG TKGLECSPST PTMNSYFYKF MINLLKRFSS
ERKLLEVRGP FIIRQLCLLL NAENIFHSMA DILLREEDLK FASTMVHALN TILLTSTELF
QLRNQLKDLK TLESQNLFCC LYRSWCHNPV TTVSLCFLTQ NYRHAYDLIQ KFGDLEVTVD
FLAEVDKLVQ LIECPIFTYL RLQLLDVKNN PYLIKALYGL LMLLPQSSAF QLLSHRLQCV
PNPELLQTED SLKAAPKSQK ADSPSIDYAE LLQHFEKVQN KHLEVRHQRS GRGDHLDRRV
VL
//
ID VAC14_HUMAN Reviewed; 782 AA.
AC Q08AM6; B3KPJ5; Q13174; Q6IA12; Q7L4Y1; Q9BW96; Q9H6V6;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-OCT-2006, sequence version 1.
DT 22-JAN-2014, entry version 70.
DE RecName: Full=Protein VAC14 homolog;
DE AltName: Full=Tax1-binding protein 2;
GN Name=VAC14; Synonyms=TAX1BP2, TRX;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-366, TISSUE SPECIFICITY, AND
RP INTERACTION WITH HTLV-I TAX.
RX PubMed=8611628; DOI=10.1016/0167-4781(96)00012-7;
RA Mireskandari A., Reid R.L., Kashanchi F., Dittmer J., Li W.B.,
RA Brady J.N.;
RT "Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic
RT virus type-I Tax1 binding protein.";
RL Biochim. Biophys. Acta 1306:9-13(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 259-782.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15542851; DOI=10.1128/MCB.24.23.10437-10447.2004;
RA Sbrissa D., Ikonomov O.C., Strakova J., Dondapati R., Mlak K.,
RA Deeb R., Silver R., Shisheva A.;
RT "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that
RT associates with and up-regulates PIKfyve phosphoinositide 5-kinase
RT activity.";
RL Mol. Cell. Biol. 24:10437-10447(2004).
RN [6]
RP INTERACTION WITH NOS1, AND MUTAGENESIS OF GLY-773; ASP-774; LEU-776;
RP ASP-777; 780-VAL--LEU-782 AND LEU-782.
RX PubMed=17161399; DOI=10.1016/j.febslet.2006.11.061;
RA Lemaire J.F., McPherson P.S.;
RT "Binding of Vac14 to neuronal nitric oxide synthase: Characterisation
RT of a new internal PDZ-recognition motif.";
RL FEBS Lett. 580:6948-6954(2006).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN THE PI(3,5)P2
RP REGULATORY COMPLEX.
RX PubMed=17556371; DOI=10.1074/jbc.M611678200;
RA Sbrissa D., Ikonomov O.C., Fu Z., Ijuin T., Gruenberg J., Takenawa T.,
RA Shisheva A.;
RT "Core protein machinery for mammalian phosphatidylinositol 3,5-
RT bisphosphate synthesis and turnover that regulates the progression of
RT endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve
RT complex.";
RL J. Biol. Chem. 282:23878-23891(2007).
RN [8]
RP SUBUNIT, IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX, AND
RP DOMAIN.
RX PubMed=18950639; DOI=10.1016/j.jmb.2008.10.009;
RA Sbrissa D., Ikonomov O.C., Fenner H., Shisheva A.;
RT "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and
RT Sac3 in a complex to promote PIKfyve activity and functionality.";
RL J. Mol. Biol. 384:766-779(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-11 AND THR-499, AND MASS
RP SPECTROMETRY.
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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
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 [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
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.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: The PI(3,5)P2 regulatory complex regulates both the
CC synthesis and turnover of phosphatidylinositol 3,5-bisphosphate
CC (PtdIns(3,5)P2). Acts as a positive activator of PIKfyve kinase
CC activity. Also required to maintain normal levels of
CC phosphatidylinositol 3-phosphate (PtdIns(3)P) and
CC phosphatidylinositol 5-phosphate (PtdIns(5)P). Plays a role in the
CC biogenesis of endosome carrier vesicles (ECV) / multivesicular
CC bodies (MVB) transport intermediates from early endosomes.
CC -!- SUBUNIT: Forms homooligomers. Component of the PI(3,5)P2
CC regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4
CC and VAC14. VAC14 nucleates the assembly of the complex and serves
CC as a scaffold. Interacts with NOS1. Interacts with HTLV-1 Tax.
CC -!- INTERACTION:
CC P29475:NOS1; NbExp=5; IntAct=EBI-2107455, EBI-7164065;
CC -!- SUBCELLULAR LOCATION: Endosome membrane. Microsome membrane (By
CC similarity). Note=Mainly associated with membranes of the late
CC endocytic pathway.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The C-terminal domain (residues 523-782) mediates
CC homomeric interactions and is necessary for the formation and
CC maintenance of the PI(3,5)P2 regulatory complex.
CC -!- SIMILARITY: Belongs to the VAC14 family.
CC -!- SIMILARITY: Contains 6 HEAT repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB03813.1; Type=Miscellaneous discrepancy; Note=Unknown C-terminal region;
CC Sequence=BAB15145.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
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DR EMBL; AK025479; BAB15145.1; ALT_INIT; mRNA.
DR EMBL; AK056433; BAG51707.1; -; mRNA.
DR EMBL; BC000536; AAH00536.2; -; mRNA.
DR EMBL; BC007214; AAH07214.2; -; mRNA.
DR EMBL; BC125108; AAI25109.1; -; mRNA.
DR EMBL; BC125109; AAI25110.1; -; mRNA.
DR EMBL; U25801; AAB03813.1; ALT_SEQ; mRNA.
DR EMBL; CR457343; CAG33624.1; -; mRNA.
DR PIR; S68091; S68091.
DR RefSeq; NP_060522.3; NM_018052.3.
DR UniGene; Hs.445061; -.
DR ProteinModelPortal; Q08AM6; -.
DR SMR; Q08AM6; 414-471.
DR IntAct; Q08AM6; 5.
DR MINT; MINT-3997917; -.
DR STRING; 9606.ENSP00000261776; -.
DR PhosphoSite; Q08AM6; -.
DR DMDM; 121940040; -.
DR PaxDb; Q08AM6; -.
DR PRIDE; Q08AM6; -.
DR Ensembl; ENST00000261776; ENSP00000261776; ENSG00000103043.
DR GeneID; 55697; -.
DR KEGG; hsa:55697; -.
DR UCSC; uc002ezm.3; human.
DR CTD; 55697; -.
DR GeneCards; GC16M070721; -.
DR HGNC; HGNC:25507; VAC14.
DR HPA; HPA027766; -.
DR MIM; 604632; gene.
DR neXtProt; NX_Q08AM6; -.
DR PharmGKB; PA142670633; -.
DR eggNOG; NOG287585; -.
DR HOVERGEN; HBG104397; -.
DR InParanoid; Q08AM6; -.
DR KO; K15305; -.
DR OMA; FKCLYGL; -.
DR OrthoDB; EOG7QNVM5; -.
DR PhylomeDB; Q08AM6; -.
DR BioCyc; MetaCyc:ENSG00000103043-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_112621; Metabolism.
DR ChiTaRS; VAC14; human.
DR GeneWiki; VAC14; -.
DR GenomeRNAi; 55697; -.
DR NextBio; 60525; -.
DR PRO; PR:Q08AM6; -.
DR ArrayExpress; Q08AM6; -.
DR Bgee; Q08AM6; -.
DR CleanEx; HS_VAC14; -.
DR Genevestigator; Q08AM6; -.
DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-KW.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0031902; C:late endosome membrane; TAS:Reactome.
DR GO; GO:0019209; F:kinase activator activity; IEA:InterPro.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.25.10.10; -; 2.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR026825; VAC14.
DR InterPro; IPR021841; VAC14_Fig4p-bd.
DR PANTHER; PTHR16023; PTHR16023; 1.
DR Pfam; PF11916; Vac14_Fig4_bd; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR PROSITE; PS50077; HEAT_REPEAT; FALSE_NEG.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Endoplasmic reticulum; Endosome;
KW Host-virus interaction; Membrane; Microsome; Phosphoprotein;
KW Reference proteome; Repeat.
FT CHAIN 1 782 Protein VAC14 homolog.
FT /FTId=PRO_0000300485.
FT REPEAT 5 42 HEAT 1.
FT REPEAT 89 126 HEAT 2.
FT REPEAT 171 208 HEAT 3.
FT REPEAT 212 249 HEAT 4.
FT REPEAT 438 475 HEAT 5.
FT REPEAT 560 598 HEAT 6.
FT REGION 773 777 Mediates interaction with the PDZ domain
FT of NOS1.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 11 11 Phosphothreonine.
FT MOD_RES 499 499 Phosphothreonine.
FT MUTAGEN 773 773 G->A: Reduces interaction with NOS1.
FT MUTAGEN 774 774 D->A: Reduces interaction with NOS1.
FT MUTAGEN 776 776 L->A: Reduces interaction with NOS1.
FT MUTAGEN 777 777 D->A: Abolishes interaction with NOS1.
FT MUTAGEN 780 782 VVL->AAA: Reduces interaction with NOS1.
FT MUTAGEN 782 782 L->G: Reduces interaction with NOS1.
FT CONFLICT 257 257 A -> P (in Ref. 3; AAB03813).
FT CONFLICT 263 263 L -> P (in Ref. 3; AAB03813).
FT CONFLICT 352 352 T -> A (in Ref. 4; CAG33624).
SQ SEQUENCE 782 AA; 87973 MW; B39AC1F4D619570F CRC64;
MNPEKDFAPL TPNIVRALND KLYEKRKVAA LEIEKLVREF VAQNNTVQIK HVIQTLSQEF
ALSQHPHSRK GGLIGLAACS IALGKDSGLY LKELIEPVLT CFNDADSRLR YYACEALYNI
VKVARGAVLP HFNVLFDGLS KLAADPDPNV KSGSELLDRL LKDIVTESNK FDLVSFIPLL
RERIYSNNQY ARQFIISWIL VLESVPDINL LDYLPEILDG LFQILGDNGK EIRKMCEVVL
GEFLKEIKKN PSSVKFAEMA NILVIHCQTT DDLIQLTAMC WMREFIQLAG RVMLPYSSGI
LTAVLPCLAY DDRKKSIKEV ANVCNQSLMK LVTPEDDELD ELRPGQRQAE PTPDDALPKQ
EGTASGGPDG SCDSSFSSGI SVFTAASTER APVTLHLDGI VQVLNCHLSD TAIGMMTRIA
VLKWLYHLYI KTPRKMFRHT DSLFPILLQT LSDESDEVIL KDLEVLAEIA SSPAGQTDDP
GPLDGPDLQA SHSELQVPTP GRAGLLNTSG TKGLECSPST PTMNSYFYKF MINLLKRFSS
ERKLLEVRGP FIIRQLCLLL NAENIFHSMA DILLREEDLK FASTMVHALN TILLTSTELF
QLRNQLKDLK TLESQNLFCC LYRSWCHNPV TTVSLCFLTQ NYRHAYDLIQ KFGDLEVTVD
FLAEVDKLVQ LIECPIFTYL RLQLLDVKNN PYLIKALYGL LMLLPQSSAF QLLSHRLQCV
PNPELLQTED SLKAAPKSQK ADSPSIDYAE LLQHFEKVQN KHLEVRHQRS GRGDHLDRRV
VL
//
MIM
604632
*RECORD*
*FIELD* NO
604632
*FIELD* TI
*604632 VAC14, S. CEREVISIAE, HOMOLOG OF; VAC14
;;ASSOCIATED REGULATOR OF PIKFYVE; ARPIKFYVE;;
read moreTAX1-BINDING PROTEIN 2; TAX1BP2;;
TAX-REACTIVE PROTEIN X; TRX
*FIELD* TX
DESCRIPTION
The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in
endosomal membranes changes dynamically with fission and fusion events
that generate or absorb intracellular transport vesicles. VAC14 is a
component of a trimolecular complex that tightly regulates the level of
PtdIns(3,5)P2. Other components of this complex are the
PtdIns(3,5)P2-synthesizing enzyme PIKFYVE (609414) and the PtdIns(3,5)P2
phosphatase FIG4 (609390). VAC14 functions as an activator of PIKFYVE
(Sbrissa et al., 2007).
CLONING
Human T-cell lymphotropic virus type-1 (HTLV-1) encodes Tax1, a 40-kD
protein that plays a key role in viral replication, transformation, and
gene regulation. By screening a human Jurkat T-cell cDNA expression
library with biologically active Tax1 protein to identify Tax1-binding
proteins, Mireskandari et al. (1996) isolated a cDNA encoding VAC14,
which they called TRX. The deduced 221-amino acid TRX protein is
predominantly hydrophilic in its C-terminal region. Northern blot
analysis of human tissues detected a major 3.5-kb TRX transcript in all
tissues examined, namely brain, heart, lung, liver, pancreas, kidney,
skeletal muscle, and placenta. However, Western blot analysis detected
TRX expression only in lymphocytes and lymphocytic-derived cell lines.
Sbrissa et al. (2004) obtained a full-length cDNA clone of human VAC14.
The deduced protein contains 782 amino acids. Western blot analysis of
human and other mammalian cell lines and of mouse tissues detected VAC14
at an apparent molecular mass of 82 kD. Fractionation and Western blot
analysis of HEK293 human embryonic kidney cells revealed endogenous
VAC14 in both cytosolic and membrane compartments. Immunohistochemical
analysis of transfected COS cells showed that human VAC14 localized
predominantly to the perinuclear region and also in more dispersed
vesicles.
HEAT repeats contain 2 antiparallel helices connected by a short loop
and provide surfaces for protein-protein interactions. Jin et al. (2008)
identified 17 HEAT repeats in mouse and human VAC14.
GENE FUNCTION
Mireskandari et al. (1996) demonstrated a specific interaction between
Tax1 and TRX by coimmunoprecipitation and Far Western blot analyses.
Using immunohistochemical analysis, Sbrissa et al. (2004) showed that
human VAC14 colocalized with mouse Pikfyve in the perinuclear region
following cotransfection of COS cells. Knockdown of VAC14 expression in
HEK293 cells did not alter cell morphology, but it sensitized cells to
brief treatment with a weak base, which resulted in formation of
cytoplasmic vacuoles and decreased production of PtsIns(3,5)P and
PtdIns(5)P by PIKFYVE. Conversely, overexpression of VAC14 in HEK293
cells increased PIKFYVE protein levels and PIKFYVE activity. Reciprocal
coimmunoprecipitation studies showed that endogenous Pikfyve and Vac14
interacted directly in rat PC12 cells, and the immunoprecipitates
synthesized PtdIns(5)P and PtdIns(3,5)P2. Sbrissa et al. (2004)
concluded that VAC14 is an activator of PIKFYVE, and thereby regulates
PtdIns(3,5)P2 synthesis and intracellular membrane homeostasis.
Using coimmunoprecipitation analysis, Sbrissa et al. (2007) showed that
endogenous PIKFYVE, ARPIKFYVE, and SAC3 (FIG4) formed a stable ternary
complex in HEK293 cells and other mammalian cell lines.
Sbrissa et al. (2008) found that ARPIKFYVE interacted with both SAC3 and
PIKFYVE and concluded that it is the principal organizer of the
PIKFYVE-ARPIKFYVE-SAC3 (PAS) complex.
MAPPING
Gross (2010) mapped the VAC14 to chromosome 16q22.1-q22.2 based on an
alignment of the VAC14 sequence (GenBank GENBANK AK056433) with the
genomic sequence (GRCh37).
Jin et al. (2008) mapped the mouse Vac14 gene to chromosome 8.
ANIMAL MODEL
Zhang et al. (2007) obtained Vac14-null mice at mendelian ratios, but
all died within 2 days of birth due to massive neurodegeneration,
particularly in the midbrain and in peripheral sensory neurons. Cell
bodies of affected neurons were vacuolated, and empty spaces were found
in areas where neurons should have been. Similar vacuoles were found in
cultured Vac14-null neurons and fibroblasts. Defects were observed in
intracellular trafficking, particularly in retrograde
endosome-to-trans-Golgi trafficking. Vac14-null cells showed abnormal
accumulation of PI(3)P and reduced levels of PI(3,5)P2 and PI(5)P
compared with wildtype cells. Overexpression of human FAB1 reversed the
effect of Vac14 deletion in mouse fibroblasts. Zhang et al. (2007) noted
that Fig4-null mice and Vac14-null mice show similar defects in PI(3,5)2
synthesis and acquire profound vacuolation in the same types of neurons.
They speculated that the neurodegeneration observed in both mouse
mutants is due to defects in metabolism of PI(3,5)P2 and/or PI(5)P, and
they concluded that VAC14 and FIG4 control FAB1 activity to maintain
normal levels of PI(3)P, PI(3,5)P2, and PI(5)P.
Mice homozygous for the spontaneous Ingls (infantile gliosis) mutation
exhibit reduced body size and diluted pigmentation. Homozygous Ingls
mice die within 3 weeks of birth and histologically show enlarged brain
ventricles. Jin et al. (2008) identified Ingls as a missense mutation
resulting in substitution of an invariant leu156 with arg within helix B
of HEAT repeat 4 in the Vac14 protein. Western blot analysis of Ingls
brains revealed normal Vac14 protein abundance, but cultured Ingls
fibroblasts showed reduced PtdIns(3,5)P2 levels. Yeast 2-hybrid analysis
showed that the leu156-to-arg mutation disrupted interaction of Vac14
with Fab1 (Pikfyve), but not Fig4.
Mutations affecting the conversion of PI3P to the signaling lipid
PI(3,5)P2 result in spongiform degeneration of mouse brain and are
associated with the human disorders Charcot-Marie-Tooth disease and
amyotrophic lateral sclerosis (ALS). Ferguson et al. (2009) reported
accumulation of the proteins Lc3II (MAP1LC3A; 601242), p62 (SQSTM1;
601530), and Lamp2 (309060) in neurons and astrocytes of mice with
mutations in 2 components of the PI(3,5)P2 regulatory complex, Fig4
(609390) and Vac14. Cytoplasmic inclusion bodies containing p62 and
ubiquitinated proteins were present in regions of the mutant brain that
underwent degeneration. Colocalization of p62 and LAMP2 in affected
cells indicated that formation or recycling of the autolysosome may be
impaired. The authors proposed a role for PI(3,5)P2 in autophagy in the
mammalian central nervous system and demonstrated that mutations
affecting PI(3,5)P2 may contribute to inclusion body disease.
*FIELD* RF
1. Ferguson, C. J.; Lenk, G. M.; Meisler, M. H.: Defective autophagy
in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum.
Molec. Genet. 18: 4868-4878, 2009.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 2/26/2010.
3. Jin, N.; Chow, C. Y.; Liu, L.; Zolov, S. N.; Bronson, R.; Davisson,
M.; Petersen, J. L.; Zhang, Y.; Park, S.; Duex, J. E.; Goldowitz,
D.; Meisler, M. H.; Weisman, L. S.: VAC14 nucleates a protein complex
essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast
and mouse. EMBO J. 27: 3221-3234, 2008.
4. Mireskandari, A.; Reid, R. L.; Kashanchi, F.; Dittmer, J.; Li,
W.-B.; Brady, J. N.: Isolation of a cDNA clone, TRX, encoding a human
T-cell lymphotrophic virus type-I Tax1 binding protein. Biochim.
Biophys. Acta 1306: 9-13, 1996.
5. Sbrissa, D.; Ikonomov, O. C.; Fenner, H.; Shisheva, A.: ArPIKfyve
homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in
a complex to promote PIKfyve activity and functionality. J. Molec.
Biol. 384: 766-779, 2008.
6. Sbrissa, D.; Ikonomov, O. C.; Fu, Z.; Ijuin, T.; Gruenberg, J.;
Takenawa, T.; Shisheva, A.: Core protein machinery for mammalian
phosphatidylinositol 3,5-bisphosphate synthesis and turnover that
regulates the progression of endosomal transport: novel Sac phosphatase
joins the ArPIKfyve-PIKfyve complex. J. Biol. Chem. 282: 23878-23891,
2007.
7. Sbrissa, D.; Ikonomov, O. C.; Strakova, J.; Dondapati, R.; Mlak,
K.; Deeb, R.; Silver, R.; Shisheva, A.: A mammalian ortholog of Saccharomyces
cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide
5-kinase activity. Molec. Cell. Biol. 24: 10437-10447, 2004.
8. Zhang, Y.; Zolov, S. N.; Chow, C. Y.; Slutsky, S. G.; Richardson,
S. C.; Piper, R. C.; Yang, B.; Nau, J. J.; Westrick, R. J.; Morrison,
S. J.; Meisler, M. H.; Weisman, L. S.: Loss of Vac14, a regulator
of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results
in neurodegeneration in mice. Proc. Nat. Acad. Sci. 104: 17518-17523,
2007.
*FIELD* CN
George E. Tiller - updated: 11/1/2010
Matthew B. Gross - updated: 2/26/2010
Patricia A. Hartz - updated: 2/23/2010
Patricia A. Hartz - updated: 8/20/2008
*FIELD* CD
Patti M. Sherman: 2/29/2000
*FIELD* ED
carol: 06/21/2013
alopez: 11/5/2010
terry: 11/1/2010
mgross: 2/26/2010
terry: 2/23/2010
mgross: 8/21/2008
terry: 8/20/2008
mgross: 3/1/2000
psherman: 2/29/2000
*RECORD*
*FIELD* NO
604632
*FIELD* TI
*604632 VAC14, S. CEREVISIAE, HOMOLOG OF; VAC14
;;ASSOCIATED REGULATOR OF PIKFYVE; ARPIKFYVE;;
read moreTAX1-BINDING PROTEIN 2; TAX1BP2;;
TAX-REACTIVE PROTEIN X; TRX
*FIELD* TX
DESCRIPTION
The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in
endosomal membranes changes dynamically with fission and fusion events
that generate or absorb intracellular transport vesicles. VAC14 is a
component of a trimolecular complex that tightly regulates the level of
PtdIns(3,5)P2. Other components of this complex are the
PtdIns(3,5)P2-synthesizing enzyme PIKFYVE (609414) and the PtdIns(3,5)P2
phosphatase FIG4 (609390). VAC14 functions as an activator of PIKFYVE
(Sbrissa et al., 2007).
CLONING
Human T-cell lymphotropic virus type-1 (HTLV-1) encodes Tax1, a 40-kD
protein that plays a key role in viral replication, transformation, and
gene regulation. By screening a human Jurkat T-cell cDNA expression
library with biologically active Tax1 protein to identify Tax1-binding
proteins, Mireskandari et al. (1996) isolated a cDNA encoding VAC14,
which they called TRX. The deduced 221-amino acid TRX protein is
predominantly hydrophilic in its C-terminal region. Northern blot
analysis of human tissues detected a major 3.5-kb TRX transcript in all
tissues examined, namely brain, heart, lung, liver, pancreas, kidney,
skeletal muscle, and placenta. However, Western blot analysis detected
TRX expression only in lymphocytes and lymphocytic-derived cell lines.
Sbrissa et al. (2004) obtained a full-length cDNA clone of human VAC14.
The deduced protein contains 782 amino acids. Western blot analysis of
human and other mammalian cell lines and of mouse tissues detected VAC14
at an apparent molecular mass of 82 kD. Fractionation and Western blot
analysis of HEK293 human embryonic kidney cells revealed endogenous
VAC14 in both cytosolic and membrane compartments. Immunohistochemical
analysis of transfected COS cells showed that human VAC14 localized
predominantly to the perinuclear region and also in more dispersed
vesicles.
HEAT repeats contain 2 antiparallel helices connected by a short loop
and provide surfaces for protein-protein interactions. Jin et al. (2008)
identified 17 HEAT repeats in mouse and human VAC14.
GENE FUNCTION
Mireskandari et al. (1996) demonstrated a specific interaction between
Tax1 and TRX by coimmunoprecipitation and Far Western blot analyses.
Using immunohistochemical analysis, Sbrissa et al. (2004) showed that
human VAC14 colocalized with mouse Pikfyve in the perinuclear region
following cotransfection of COS cells. Knockdown of VAC14 expression in
HEK293 cells did not alter cell morphology, but it sensitized cells to
brief treatment with a weak base, which resulted in formation of
cytoplasmic vacuoles and decreased production of PtsIns(3,5)P and
PtdIns(5)P by PIKFYVE. Conversely, overexpression of VAC14 in HEK293
cells increased PIKFYVE protein levels and PIKFYVE activity. Reciprocal
coimmunoprecipitation studies showed that endogenous Pikfyve and Vac14
interacted directly in rat PC12 cells, and the immunoprecipitates
synthesized PtdIns(5)P and PtdIns(3,5)P2. Sbrissa et al. (2004)
concluded that VAC14 is an activator of PIKFYVE, and thereby regulates
PtdIns(3,5)P2 synthesis and intracellular membrane homeostasis.
Using coimmunoprecipitation analysis, Sbrissa et al. (2007) showed that
endogenous PIKFYVE, ARPIKFYVE, and SAC3 (FIG4) formed a stable ternary
complex in HEK293 cells and other mammalian cell lines.
Sbrissa et al. (2008) found that ARPIKFYVE interacted with both SAC3 and
PIKFYVE and concluded that it is the principal organizer of the
PIKFYVE-ARPIKFYVE-SAC3 (PAS) complex.
MAPPING
Gross (2010) mapped the VAC14 to chromosome 16q22.1-q22.2 based on an
alignment of the VAC14 sequence (GenBank GENBANK AK056433) with the
genomic sequence (GRCh37).
Jin et al. (2008) mapped the mouse Vac14 gene to chromosome 8.
ANIMAL MODEL
Zhang et al. (2007) obtained Vac14-null mice at mendelian ratios, but
all died within 2 days of birth due to massive neurodegeneration,
particularly in the midbrain and in peripheral sensory neurons. Cell
bodies of affected neurons were vacuolated, and empty spaces were found
in areas where neurons should have been. Similar vacuoles were found in
cultured Vac14-null neurons and fibroblasts. Defects were observed in
intracellular trafficking, particularly in retrograde
endosome-to-trans-Golgi trafficking. Vac14-null cells showed abnormal
accumulation of PI(3)P and reduced levels of PI(3,5)P2 and PI(5)P
compared with wildtype cells. Overexpression of human FAB1 reversed the
effect of Vac14 deletion in mouse fibroblasts. Zhang et al. (2007) noted
that Fig4-null mice and Vac14-null mice show similar defects in PI(3,5)2
synthesis and acquire profound vacuolation in the same types of neurons.
They speculated that the neurodegeneration observed in both mouse
mutants is due to defects in metabolism of PI(3,5)P2 and/or PI(5)P, and
they concluded that VAC14 and FIG4 control FAB1 activity to maintain
normal levels of PI(3)P, PI(3,5)P2, and PI(5)P.
Mice homozygous for the spontaneous Ingls (infantile gliosis) mutation
exhibit reduced body size and diluted pigmentation. Homozygous Ingls
mice die within 3 weeks of birth and histologically show enlarged brain
ventricles. Jin et al. (2008) identified Ingls as a missense mutation
resulting in substitution of an invariant leu156 with arg within helix B
of HEAT repeat 4 in the Vac14 protein. Western blot analysis of Ingls
brains revealed normal Vac14 protein abundance, but cultured Ingls
fibroblasts showed reduced PtdIns(3,5)P2 levels. Yeast 2-hybrid analysis
showed that the leu156-to-arg mutation disrupted interaction of Vac14
with Fab1 (Pikfyve), but not Fig4.
Mutations affecting the conversion of PI3P to the signaling lipid
PI(3,5)P2 result in spongiform degeneration of mouse brain and are
associated with the human disorders Charcot-Marie-Tooth disease and
amyotrophic lateral sclerosis (ALS). Ferguson et al. (2009) reported
accumulation of the proteins Lc3II (MAP1LC3A; 601242), p62 (SQSTM1;
601530), and Lamp2 (309060) in neurons and astrocytes of mice with
mutations in 2 components of the PI(3,5)P2 regulatory complex, Fig4
(609390) and Vac14. Cytoplasmic inclusion bodies containing p62 and
ubiquitinated proteins were present in regions of the mutant brain that
underwent degeneration. Colocalization of p62 and LAMP2 in affected
cells indicated that formation or recycling of the autolysosome may be
impaired. The authors proposed a role for PI(3,5)P2 in autophagy in the
mammalian central nervous system and demonstrated that mutations
affecting PI(3,5)P2 may contribute to inclusion body disease.
*FIELD* RF
1. Ferguson, C. J.; Lenk, G. M.; Meisler, M. H.: Defective autophagy
in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum.
Molec. Genet. 18: 4868-4878, 2009.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 2/26/2010.
3. Jin, N.; Chow, C. Y.; Liu, L.; Zolov, S. N.; Bronson, R.; Davisson,
M.; Petersen, J. L.; Zhang, Y.; Park, S.; Duex, J. E.; Goldowitz,
D.; Meisler, M. H.; Weisman, L. S.: VAC14 nucleates a protein complex
essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast
and mouse. EMBO J. 27: 3221-3234, 2008.
4. Mireskandari, A.; Reid, R. L.; Kashanchi, F.; Dittmer, J.; Li,
W.-B.; Brady, J. N.: Isolation of a cDNA clone, TRX, encoding a human
T-cell lymphotrophic virus type-I Tax1 binding protein. Biochim.
Biophys. Acta 1306: 9-13, 1996.
5. Sbrissa, D.; Ikonomov, O. C.; Fenner, H.; Shisheva, A.: ArPIKfyve
homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in
a complex to promote PIKfyve activity and functionality. J. Molec.
Biol. 384: 766-779, 2008.
6. Sbrissa, D.; Ikonomov, O. C.; Fu, Z.; Ijuin, T.; Gruenberg, J.;
Takenawa, T.; Shisheva, A.: Core protein machinery for mammalian
phosphatidylinositol 3,5-bisphosphate synthesis and turnover that
regulates the progression of endosomal transport: novel Sac phosphatase
joins the ArPIKfyve-PIKfyve complex. J. Biol. Chem. 282: 23878-23891,
2007.
7. Sbrissa, D.; Ikonomov, O. C.; Strakova, J.; Dondapati, R.; Mlak,
K.; Deeb, R.; Silver, R.; Shisheva, A.: A mammalian ortholog of Saccharomyces
cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide
5-kinase activity. Molec. Cell. Biol. 24: 10437-10447, 2004.
8. Zhang, Y.; Zolov, S. N.; Chow, C. Y.; Slutsky, S. G.; Richardson,
S. C.; Piper, R. C.; Yang, B.; Nau, J. J.; Westrick, R. J.; Morrison,
S. J.; Meisler, M. H.; Weisman, L. S.: Loss of Vac14, a regulator
of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results
in neurodegeneration in mice. Proc. Nat. Acad. Sci. 104: 17518-17523,
2007.
*FIELD* CN
George E. Tiller - updated: 11/1/2010
Matthew B. Gross - updated: 2/26/2010
Patricia A. Hartz - updated: 2/23/2010
Patricia A. Hartz - updated: 8/20/2008
*FIELD* CD
Patti M. Sherman: 2/29/2000
*FIELD* ED
carol: 06/21/2013
alopez: 11/5/2010
terry: 11/1/2010
mgross: 2/26/2010
terry: 2/23/2010
mgross: 8/21/2008
terry: 8/20/2008
mgross: 3/1/2000
psherman: 2/29/2000