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8.A.9.2.2
The Slc3A2 (CD98hc; 4F2hc) accessory protein facilitates transport of amino acids and polyamines (putrescine/spermidine) (Uemura et al. 2008). 4F2hc stabilizes GLUT1 (2.A.1.1.28) and increase glucose transport activity (Ohno et al., 2011).  It forms a heterodimer with glycoprotein CD98 (LAT1; SLC7A5), and contributes to tumorigenesis (Estrach et al. 2014).  CD98hc also modulates integrin signaling, plays a role in cell-to-cell fusion, and is essential for Brucella infection (Keriel et al. 2015). Hepatitis C virus (HCV) exploits SLC3A2 for viral propagation, and upregulation of SLC3A2 may contribute to HCV-mediated pathogenesis (Nguyen et al. 2018). ZEB1, a transcriptional repressor (P37275), promotes chemoresistance to cisplatin in ovarian cancer cells by suppressing SLC3A2 (Cui et al. 2018). SLC3A2/CD98hc and its light chain subunits constitute the heterodimeric transmembrane complexes that mediate amino acid transport and regulate MTOR and macroautophagy/autophagy (Digomann et al. 2019). It forms a tight complex with beta1 integrin (TC# 9.B.87.1.8) and TrpV4 (TC# 1.A.4.2.5) in focal adhesions where mechanochemical conversion takes place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis revealed that forces applied to beta1 integrin must be transmitted from its cytoplasmic C-terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultra-rapid, force-induced, channel activation within the focal adhesion (Potla et al. 2020).

Accession Number:P08195
Protein Name:4F2 cell-surface antigen heavy chain
Length:630
Molecular Weight:67994.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:2
Location1 / Topology2 / Orientation3: Apical cell membrane1 / Single-pass type II membrane protein2
Substrate NONE

Cross database links:

RefSeq: NP_001012679.1    NP_001012680.1    NP_001012681.1    NP_001012682.1    NP_001013269.1    NP_002385.3   
Entrez Gene ID: 6520   
Pfam: PF00128   
OMIM: 158070  gene
BioCyc: MetaCyc:MONOMER-15188   
KEGG: hsa:6520    hsa:6520   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0009986 C:cell surface
GO:0016021 C:integral to membrane
GO:0042470 C:melanosome
GO:0005432 F:calcium:sodium antiporter activity
GO:0003824 F:catalytic activity
GO:0043169 F:cation binding
GO:0015175 F:neutral amino acid transmembrane transporte...
GO:0005515 F:protein binding
GO:0006816 P:calcium ion transport
GO:0005975 P:carbohydrate metabolic process
GO:0016049 P:cell growth
GO:0060356 P:leucine import
GO:0015827 P:tryptophan transport
GO:0005886 C:plasma membrane
GO:0015175 F:neutral amino acid transmembrane transporter activity
GO:0007596 P:blood coagulation
GO:0050900 P:leukocyte migration

References (71)

[1] “Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth.”  Quackenbush E.et.al.   3476959
[2] “Primary structure of the human 4F2 antigen heavy chain predicts a transmembrane protein with a cytoplasmic NH2 terminus.”  Teixeira S.et.al.   3036867
[3] “Cloning, sequence analysis, and expression of the large subunit of the human lymphocyte activation antigen 4F2.”  Lumadue J.A.et.al.   3480538
[4] “Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation.”  Gottesdiener K.M.et.al.   3265470
[5] “Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.”  Yanagida O.et.al.   11557028
[6] “Human chromosome 11 DNA sequence and analysis including novel gene identification.”  Taylor T.D.et.al.   16554811
[7] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[8] “Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance.”  Torrents D.et.al.   9829974
[9] “Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.”  Mastroberardino L.et.al.   9751058
[10] “Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.”  Pfeiffer R.et.al.   9878049
[11] “The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine.”  Broeer A.et.al.   10903140
[12] “Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains.”  Broeer A.et.al.   11311135
[13] “Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta.”  Ritchie J.W.A.et.al.   11389679
[14] “Beta1 integrins show specific association with CD98 protein in low density membranes.”  Kolesnikova T.V.et.al.   11696247
[15] “Thyroid hormone transport by the heterodimeric human system L amino acid transporter.”  Friesema E.C.H.et.al.   11564694
[16] “Expression and regulation of 4F2hc and hLAT1 in human trophoblasts.”  Okamoto Y.et.al.   11742812
[17] “Molecular cloning and characterization of CT120, a novel membrane-associated gene involved in amino acid transport and glutathione metabolism.”  He X.H.et.al.   12270127
[18] “Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2.”  Simmons-Willis T.A.et.al.   12117417
[19] “Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells.”  Kim D.K.et.al.   12225859
[20] “Cluster analysis of an extensive human breast cancer cell line protein expression map database.”  Harris R.A.et.al.   11840567
[21] “Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium.”  Arancibia-Garavilla Y.et.al.   14603368
[22] “CD98 and intracellular adhesion molecule I regulate the activity of amino acid transporter LAT-2 in polarized intestinal epithelia.”  Liu X.et.al.   12716892
[23] “Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.”  Zhang H.et.al.   12754519
[24] “L-type amino acid transporter 1-mediated L-leucine transport at the inner blood-retinal barrier.”  Tomi M.et.al.   15980244
[25] “Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols.”  Li S.et.al.   15769744
[26] “Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.”  Liu T.et.al.   16335952
[27] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen J.V.et.al.   17081983
[28] “L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors.”  Nawashiro H.et.al.   16496379
[29] “Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.”  Chi A.et.al.   17081065
[30] “Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry.”  Meierhofer D.et.al.   18781797
[31] “Ecto-phosphorylation of CD98 regulates cell-cell interactions.”  Nguyen H.T.T.et.al.   19065266
[32] “Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.”  Chen R.et.al.   19159218
[33] “Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins.”  Wollscheid B.et.al.   19349973
[34] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[35] “The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane.”  Fort J.et.al.   17724034
[36] “Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth.”  Quackenbush E.et.al.   3476959
[37] “Primary structure of the human 4F2 antigen heavy chain predicts a transmembrane protein with a cytoplasmic NH2 terminus.”  Teixeira S.et.al.   3036867
[38] “Cloning, sequence analysis, and expression of the large subunit of the human lymphocyte activation antigen 4F2.”  Lumadue J.A.et.al.   3480538
[39] “Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation.”  Gottesdiener K.M.et.al.   3265470
[40] “Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.”  Yanagida O.et.al.   11557028
[41] “Human chromosome 11 DNA sequence and analysis including novel gene identification.”  Taylor T.D.et.al.   16554811
[42] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[43] “Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance.”  Torrents D.et.al.   9829974
[44] “Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.”  Mastroberardino L.et.al.   9751058
[45] “Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.”  Pfeiffer R.et.al.   9878049
[46] “The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine.”  Broeer A.et.al.   10903140
[47] “Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains.”  Broeer A.et.al.   11311135
[48] “Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta.”  Ritchie J.W.A.et.al.   11389679
[49] “Beta1 integrins show specific association with CD98 protein in low density membranes.”  Kolesnikova T.V.et.al.   11696247
[50] “Thyroid hormone transport by the heterodimeric human system L amino acid transporter.”  Friesema E.C.H.et.al.   11564694
[51] “Expression and regulation of 4F2hc and hLAT1 in human trophoblasts.”  Okamoto Y.et.al.   11742812
[52] “Molecular cloning and characterization of CT120, a novel membrane-associated gene involved in amino acid transport and glutathione metabolism.”  He X.H.et.al.   12270127
[53] “Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2.”  Simmons-Willis T.A.et.al.   12117417
[54] “Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells.”  Kim D.K.et.al.   12225859
[55] “Cluster analysis of an extensive human breast cancer cell line protein expression map database.”  Harris R.A.et.al.   11840567
[56] “Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium.”  Arancibia-Garavilla Y.et.al.   14603368
[57] “CD98 and intracellular adhesion molecule I regulate the activity of amino acid transporter LAT-2 in polarized intestinal epithelia.”  Liu X.et.al.   12716892
[58] “Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.”  Zhang H.et.al.   12754519
[59] “L-type amino acid transporter 1-mediated L-leucine transport at the inner blood-retinal barrier.”  Tomi M.et.al.   15980244
[60] “Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols.”  Li S.et.al.   15769744
[61] “Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.”  Liu T.et.al.   16335952
[62] “Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.”  Olsen J.V.et.al.   17081983
[63] “L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors.”  Nawashiro H.et.al.   16496379
[64] “Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.”  Chi A.et.al.   17081065
[65] “Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry.”  Meierhofer D.et.al.   18781797
[66] “Ecto-phosphorylation of CD98 regulates cell-cell interactions.”  Nguyen H.T.T.et.al.   19065266
[67] “Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.”  Chen R.et.al.   19159218
[68] “Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins.”  Wollscheid B.et.al.   19349973
[69] “Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.”  Mayya V.et.al.   19690332
[70] “Initial characterization of the human central proteome.”  Burkard T.R.et.al.   21269460
[71] “The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane.”  Fort J.et.al.   17724034
Structure:
2DH2   2DH3   6JMQ   6JMR   6S8V     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MELQPPEASI AVVSIPRQLP GSHSEAGVQG LSAGDDSELG SHCVAQTGLE LLASGDPLPS 
61:	ASQNAEMIET GSDCVTQAGL QLLASSDPPA LASKNAEVTG TMSQDTEVDM KEVELNELEP 
121:	EKQPMNAASG AAMSLAGAEK NGLVKIKVAE DEAEAAAAAK FTGLSKEELL KVAGSPGWVR 
181:	TRWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QAFQGHGAGN 
241:	LAGLKGRLDY LSSLKVKGLV LGPIHKNQKD DVAQTDLLQI DPNFGSKEDF DSLLQSAKKK 
301:	SIRVILDLTP NYRGENSWFS TQVDTVATKV KDALEFWLQA GVDGFQVRDI ENLKDASSFL 
361:	AEWQNITKGF SEDRLLIAGT NSSDLQQILS LLESNKDLLL TSSYLSDSGS TGEHTKSLVT 
421:	QYLNATGNRW CSWSLSQARL LTSFLPAQLL RLYQLMLFTL PGTPVFSYGD EIGLDAAALP 
481:	GQPMEAPVML WDESSFPDIP GAVSANMTVK GQSEDPGSLL SLFRRLSDQR SKERSLLHGD 
541:	FHAFSAGPGL FSYIRHWDQN ERFLVVLNFG DVGLSAGLQA SDLPASASLP AKADLLLSTQ 
601:	PGREEGSPLE LERLKLEPHE GLLLRFPYAA