LAP4B_HUMAN
ID LAP4B_HUMAN Reviewed; 317 AA.
AC Q86VI4; Q3ZCV5; Q7L909; Q86VH8; Q9H060;
DT 19-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 10-OCT-2018, sequence version 2.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Lysosomal-associated transmembrane protein 4B {ECO:0000305};
DE AltName: Full=Lysosome-associated transmembrane protein 4-beta {ECO:0000303|PubMed:12902989};
GN Name=LAPTM4B {ECO:0000312|HGNC:HGNC:13646}; ORFNames=PSEC0001;
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 SUBCELLULAR LOCATION.
RX PubMed=12902989; DOI=10.1038/sj.onc.1206832;
RA Shao G.-Z., Zhou R.L., Zhang Q.Y., Zhang Y., Liu J.J., Rui J.A., Wei X.,
RA Ye D.X.;
RT "Molecular cloning and characterization of LAPTM4B, a novel gene
RT upregulated in hepatocellular carcinoma.";
RL Oncogene 22:5060-5069(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Hogue D.L.;
RL Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=16303743; DOI=10.1093/dnares/12.2.117;
RA Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J.,
RA Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S.,
RA Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.,
RA Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S.,
RA Isogai T.;
RT "Signal sequence and keyword trap in silico for selection of full-length
RT human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA
RT libraries.";
RL DNA Res. 12:117-126(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Hippocampus, Lung, and Retinoblastoma;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 31-317 (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [6]
RP INTERACTION WITH MCOLN1, SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, AND
RP FUNCTION.
RX PubMed=21224396; DOI=10.1242/jcs.076240;
RA Vergarajauregui S., Martina J.A., Puertollano R.;
RT "LAPTMs regulate lysosomal function and interact with mucolipin 1: new
RT clues for understanding mucolipidosis type IV.";
RL J. Cell Sci. 124:459-468(2011).
RN [7]
RP SUBCELLULAR LOCATION, INTERACTION WITH NEDD4, UBIQUITINATION, MUTAGENESIS
RP OF PRO-296 AND PRO-312, AND REGION.
RX PubMed=22096579; DOI=10.1371/journal.pone.0027478;
RA Milkereit R., Rotin D.;
RT "A role for the ubiquitin ligase Nedd4 in membrane sorting of LAPTM4
RT proteins.";
RL PLoS ONE 6:E27478-E27478(2011).
RN [8]
RP INTERACTION WITH PIP5K1C AND HGS, SUBCELLULAR LOCATION, FUNCTION, AND
RP MUTAGENESIS OF PRO-296 AND PRO-312.
RX PubMed=25588945; DOI=10.15252/embj.201489425;
RA Tan X., Sun Y., Thapa N., Liao Y., Hedman A.C., Anderson R.A.;
RT "LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling,
RT lysosomal sorting, and degradation.";
RL EMBO J. 34:475-490(2015).
RN [9]
RP INTERACTION WITH LRRC32, AND FUNCTION.
RX PubMed=26126825; DOI=10.1074/jbc.m115.655340;
RA Huygens C., Lienart S., Dedobbeleer O., Stockis J., Gauthy E., Coulie P.G.,
RA Lucas S.;
RT "Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases
RT Transforming Growth Factor beta1 (TGF-beta1) Production in Human Regulatory
RT T Cells.";
RL J. Biol. Chem. 290:20105-20116(2015).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=26280656; DOI=10.1038/nchembio.1889;
RA Blom T., Li S., Dichlberger A., Baeck N., Kim Y.A., Loizides-Mangold U.,
RA Riezman H., Bittman R., Ikonen E.;
RT "LAPTM4B facilitates late endosomal ceramide export to control cell death
RT pathways.";
RL Nat. Chem. Biol. 11:799-806(2015).
RN [11]
RP INTERACTION WITH SLC3A2 AND SLC7A5, AND FUNCTION.
RX PubMed=25998567; DOI=10.1038/ncomms8250;
RA Milkereit R., Persaud A., Vanoaica L., Guetg A., Verrey F., Rotin D.;
RT "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes
RT mTORC1 activation.";
RL Nat. Commun. 6:7250-7250(2015).
RN [12]
RP INTERACTION WITH BECN1 AND EGFR.
RX PubMed=28479384; DOI=10.1016/j.gene.2017.05.006;
RA Tian M., Chen Y., Tian D., Qiao X., Ma Z., Li J.;
RT "Beclin1 antagonizes LAPTM4B-mediated EGFR overactivation in gastric cancer
RT cells.";
RL Gene 626:48-53(2017).
CC -!- FUNCTION: Required for optimal lysosomal function (PubMed:21224396).
CC Blocks EGF-stimulated EGFR intraluminal sorting and degradation.
CC Conversely by binding with the phosphatidylinositol 4,5-bisphosphate,
CC regulates its PIP5K1C interaction, inhibits HGS ubiquitination and
CC relieves LAPTM4B inhibition of EGFR degradation (PubMed:25588945).
CC Recruits SLC3A2 and SLC7A5 (the Leu transporter) to the lysosome,
CC promoting entry of leucine and other essential amino acid (EAA) into
CC the lysosome, stimulating activation of proton-transporting vacuolar
CC (V)-ATPase protein pump (V-ATPase) and hence mTORC1 activation
CC (PubMed:25998567). Plays a role as negative regulator of TGFB1
CC production in regulatory T cells (PubMed:26126825). Binds ceramide and
CC facilitates its exit from late endosome in order to control cell death
CC pathways (PubMed:26280656). {ECO:0000269|PubMed:21224396,
CC ECO:0000269|PubMed:25588945, ECO:0000269|PubMed:25998567,
CC ECO:0000269|PubMed:26126825, ECO:0000269|PubMed:26280656}.
CC -!- SUBUNIT: Homooligomer; upon reaching the lysosomes (PubMed:21224396).
CC Interacts with MCOLN1 (PubMed:21224396). Interacts with NEDD4; may play
CC a role in the lysosomal sorting of LAPTM4B; enhances HGS association
CC with NEDD4; mediates inhibition of EGFR degradation (PubMed:22096579,
CC PubMed:25588945). Interacts with PIP5K1C; promotes SNX5 association
CC with LAPTM4B; kinase activity of PIP5K1C is required; interaction is
CC regulated by phosphatidylinositol 4,5-bisphosphate generated by PIP5K1C
CC (PubMed:25588945). Interacts with HGS; promotes HGS ubiquitination
CC (PubMed:25588945). Interacts with SNX5 (PubMed:25588945). Interacts
CC with SLC3A2 AND SLC7A5; recruits SLC3A2 and SLC7A5 to lysosomes to
CC promote leucine uptake into these organelles and is required for mTORC1
CC activation (PubMed:25998567). Interacts with LRRC32; decreases TGFB1
CC production in regulatory T cells (PubMed:26126825). Interacts with
CC BECN1; competes with EGFR for LAPTM4B binding; regulates EGFR activity
CC (PubMed:28479384). Interacts with EGFR; positively correlates with EGFR
CC activation (PubMed:28479384). {ECO:0000269|PubMed:21224396,
CC ECO:0000269|PubMed:22096579, ECO:0000269|PubMed:25588945,
CC ECO:0000269|PubMed:25998567, ECO:0000269|PubMed:26126825,
CC ECO:0000269|PubMed:28479384}.
CC -!- INTERACTION:
CC Q86VI4; P08183: ABCB1; NbExp=2; IntAct=EBI-3267258, EBI-1057359;
CC Q86VI4; Q99675: CGRRF1; NbExp=3; IntAct=EBI-3267258, EBI-2130213;
CC Q86VI4; Q4LDR2: CTXN3; NbExp=3; IntAct=EBI-3267258, EBI-12019274;
CC Q86VI4; Q8NBI2: CYB561A3; NbExp=3; IntAct=EBI-3267258, EBI-10269179;
CC Q86VI4; P00533: EGFR; NbExp=10; IntAct=EBI-3267258, EBI-297353;
CC Q86VI4; P54849: EMP1; NbExp=3; IntAct=EBI-3267258, EBI-4319440;
CC Q86VI4; Q96A65: EXOC4; NbExp=2; IntAct=EBI-3267258, EBI-355383;
CC Q86VI4; P48165: GJA8; NbExp=3; IntAct=EBI-3267258, EBI-17458373;
CC Q86VI4; Q8TED1: GPX8; NbExp=3; IntAct=EBI-3267258, EBI-11721746;
CC Q86VI4; P17181: IFNAR1; NbExp=3; IntAct=EBI-3267258, EBI-1547250;
CC Q86VI4; P24593: IGFBP5; NbExp=3; IntAct=EBI-3267258, EBI-720480;
CC Q86VI4; Q6UXK2: ISLR2; NbExp=3; IntAct=EBI-3267258, EBI-1266923;
CC Q86VI4; Q9H2K0: MTIF3; NbExp=3; IntAct=EBI-3267258, EBI-3923617;
CC Q86VI4; Q58DX5: NAALADL2; NbExp=3; IntAct=EBI-3267258, EBI-10178964;
CC Q86VI4; Q02297-10: NRG1; NbExp=3; IntAct=EBI-3267258, EBI-12842334;
CC Q86VI4; Q2M2E3: ODF4; NbExp=3; IntAct=EBI-3267258, EBI-12382569;
CC Q86VI4; Q14108: SCARB2; NbExp=3; IntAct=EBI-3267258, EBI-1564650;
CC Q86VI4; Q8N661: TMEM86B; NbExp=3; IntAct=EBI-3267258, EBI-2548832;
CC Q86VI4; A5PKU2: TUSC5; NbExp=3; IntAct=EBI-3267258, EBI-11988865;
CC Q86VI4; Q96FB2; NbExp=3; IntAct=EBI-3267258, EBI-2857623;
CC Q86VI4-3; P27986: PIK3R1; NbExp=2; IntAct=EBI-3267286, EBI-79464;
CC -!- SUBCELLULAR LOCATION: Endomembrane system
CC {ECO:0000269|PubMed:12902989}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:12902989}. Late endosome membrane
CC {ECO:0000269|PubMed:21224396, ECO:0000269|PubMed:22096579,
CC ECO:0000269|PubMed:25588945}. Cell membrane
CC {ECO:0000269|PubMed:22096579}. Cell projection
CC {ECO:0000269|PubMed:22096579}. Lysosome membrane
CC {ECO:0000269|PubMed:21224396, ECO:0000269|PubMed:22096579}. Endosome
CC membrane. Endosome, multivesicular body membrane
CC {ECO:0000269|PubMed:26280656}. Endosome, multivesicular body lumen
CC {ECO:0000269|PubMed:26280656}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q86VI4-3; Sequence=Displayed;
CC Name=2;
CC IsoId=Q86VI4-2; Sequence=VSP_059831;
CC -!- PTM: Undergoes proteolytic cleavage following delivery to the
CC lysosomes. {ECO:0000269|PubMed:21224396}.
CC -!- PTM: Ubiquitinated by NEDD4. {ECO:0000269|PubMed:22096579}.
CC -!- SIMILARITY: Belongs to the LAPTM4/LAPTM5 transporter family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAO84265.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};
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DR EMBL; AF527412; AAP14034.1; -; mRNA.
DR EMBL; AY057051; AAL17908.2; -; mRNA.
DR EMBL; AY261384; AAO84265.1; ALT_SEQ; mRNA.
DR EMBL; AF317417; AAK69595.1; -; mRNA.
DR EMBL; AK075326; BAC11549.1; -; mRNA.
DR EMBL; BC014129; AAH14129.1; -; mRNA.
DR EMBL; BC031021; AAH31021.1; -; mRNA.
DR EMBL; BC038117; AAH38117.1; -; mRNA.
DR EMBL; AL136942; CAB66876.2; -; mRNA.
DR CCDS; CCDS6275.1; -. [Q86VI4-2]
DR RefSeq; NP_060877.3; NM_018407.4. [Q86VI4-2]
DR AlphaFoldDB; Q86VI4; -.
DR BioGRID; 120633; 48.
DR IntAct; Q86VI4; 38.
DR MINT; Q86VI4; -.
DR STRING; 9606.ENSP00000402301; -.
DR TCDB; 2.A.74.1.3; the 4 tms multidrug endosomal transporter (met) family.
DR iPTMnet; Q86VI4; -.
DR PhosphoSitePlus; Q86VI4; -.
DR SwissPalm; Q86VI4; -.
DR BioMuta; LAPTM4B; -.
DR DMDM; 74714056; -.
DR EPD; Q86VI4; -.
DR jPOST; Q86VI4; -.
DR MassIVE; Q86VI4; -.
DR MaxQB; Q86VI4; -.
DR PaxDb; Q86VI4; -.
DR PeptideAtlas; Q86VI4; -.
DR PRIDE; Q86VI4; -.
DR ProteomicsDB; 70025; -. [Q86VI4-2]
DR ProteomicsDB; 70026; -. [Q86VI4-3]
DR Antibodypedia; 26024; 160 antibodies from 27 providers.
DR DNASU; 55353; -.
DR Ensembl; ENST00000445593.6; ENSP00000402301.2; ENSG00000104341.17. [Q86VI4-3]
DR Ensembl; ENST00000521545.7; ENSP00000428409.1; ENSG00000104341.17. [Q86VI4-2]
DR Ensembl; ENST00000619747.1; ENSP00000482533.1; ENSG00000104341.17. [Q86VI4-3]
DR GeneID; 55353; -.
DR KEGG; hsa:55353; -.
DR MANE-Select; ENST00000521545.7; ENSP00000428409.1; NM_018407.6; NP_060877.4. [Q86VI4-2]
DR UCSC; uc003yia.4; human. [Q86VI4-3]
DR CTD; 55353; -.
DR DisGeNET; 55353; -.
DR GeneCards; LAPTM4B; -.
DR HGNC; HGNC:13646; LAPTM4B.
DR HPA; ENSG00000104341; Tissue enhanced (retina).
DR MIM; 613296; gene.
DR neXtProt; NX_Q86VI4; -.
DR OpenTargets; ENSG00000104341; -.
DR PharmGKB; PA128395785; -.
DR VEuPathDB; HostDB:ENSG00000104341; -.
DR eggNOG; ENOG502QSAX; Eukaryota.
DR GeneTree; ENSGT00940000153446; -.
DR HOGENOM; CLU_065068_0_0_1; -.
DR InParanoid; Q86VI4; -.
DR OMA; YDDPANG; -.
DR OrthoDB; 1145926at2759; -.
DR PhylomeDB; Q86VI4; -.
DR TreeFam; TF330843; -.
DR PathwayCommons; Q86VI4; -.
DR SignaLink; Q86VI4; -.
DR BioGRID-ORCS; 55353; 6 hits in 1072 CRISPR screens.
DR ChiTaRS; LAPTM4B; human.
DR GeneWiki; LAPTM4B; -.
DR GenomeRNAi; 55353; -.
DR Pharos; Q86VI4; Tbio.
DR PRO; PR:Q86VI4; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q86VI4; protein.
DR Bgee; ENSG00000104341; Expressed in pigmented layer of retina and 210 other tissues.
DR ExpressionAtlas; Q86VI4; baseline and differential.
DR Genevisible; Q86VI4; HS.
DR GO; GO:0042995; C:cell projection; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0032585; C:multivesicular body membrane; IDA:UniProtKB.
DR GO; GO:0097487; C:multivesicular body, internal vesicle; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0097001; F:ceramide binding; IDA:UniProtKB.
DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB.
DR GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB.
DR GO; GO:0032509; P:endosome transport via multivesicular body sorting pathway; IDA:UniProtKB.
DR GO; GO:1905166; P:negative regulation of lysosomal protein catabolic process; IMP:UniProtKB.
DR GO; GO:0032911; P:negative regulation of transforming growth factor beta1 production; IDA:UniProtKB.
DR GO; GO:0097213; P:regulation of lysosomal membrane permeability; IMP:UniProtKB.
DR GO; GO:1905671; P:regulation of lysosome organization; IMP:UniProtKB.
DR InterPro; IPR004687; LAPTM4/5.
DR InterPro; IPR018401; Lysosomal-assoc_TM_prot4B.
DR PANTHER; PTHR12479:SF6; PTHR12479:SF6; 1.
DR Pfam; PF03821; Mtp; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Cell projection; Endosome; Lysosome;
KW Membrane; Reference proteome; Transmembrane; Transmembrane helix;
KW Transport; Ubl conjugation.
FT CHAIN 1..317
FT /note="Lysosomal-associated transmembrane protein 4B"
FT /id="PRO_0000249721"
FT TRANSMEM 117..137
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 163..183
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 191..211
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 244..264
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 25..73
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 205..221
FT /note="Required for NEDD4 interaction"
FT /evidence="ECO:0000269|PubMed:22096579"
FT COMPBIAS 36..65
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..91
FT /note="Missing (in isoform 2)"
FT /id="VSP_059831"
FT MUTAGEN 296
FT /note="P->A: Abolishes binding to NEDD4; when associated
FT with A-312. Increases localization to cell membrane; when
FT associated with A-312. Retains association with HGS and
FT enhances PIP5K1C interaction; when associated with A-312.
FT Does not affect EGFR degradation; when associated with A-
FT 312."
FT /evidence="ECO:0000269|PubMed:22096579,
FT ECO:0000269|PubMed:25588945"
FT MUTAGEN 312
FT /note="P->A: Abolishes binding to NEDD4; when associated
FT with A-296. Increases localization to cell membrane; when
FT associated with A-296. Retains association with HGS and
FT enhances PIP5K1C interaction; when associated with A-296.
FT Does not affect EGFR degradation; when associated with A-
FT 296."
FT /evidence="ECO:0000269|PubMed:22096579,
FT ECO:0000269|PubMed:25588945"
FT CONFLICT 32
FT /note="D -> R (in Ref. 5; CAB66876)"
FT /evidence="ECO:0000305"
FT CONFLICT 85
FT /note="R -> S (in Ref. 4; AAH38117)"
FT /evidence="ECO:0000305"
FT CONFLICT 179
FT /note="M -> T (in Ref. 4; AAH38117)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 317 AA; 35123 MW; 4E93093E066BE948 CRC64;
MTSRTRVTWP SPPRPLPVPA AAAVAFGAKG TDPAEARSSR GIEEAGPRAH GRAGREPERR
RSRQQRRGGL QARRSTLLKT CARARATAPG AMKMVAPWTR FYSNSCCLCC HVRTGTILLG
VWYLIINAVV LLILLSALAD PDQYNFSSSE LGGDFEFMDD ANMCIAIAIS LLMILICAMA
TYGAYKQRAA WIIPFFCYQI FDFALNMLVA ITVLIYPNSI QEYIRQLPPN FPYRDDVMSV
NPTCLVLIIL LFISIILTFK GYLISCVWNC YRYINGRNSS DVLVYVTSND TTVLLPPYDD
ATVNGAAKEP PPPYVSA
