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J Biol Chem, Vol. 273, Issue 49, 32437-32445, December 4, 1998
From the Departament de Bioquímica i Biologia Molecular and
the We have identified a new human
cDNA (y+L amino acid transporter-1
(y+LAT-1)) that induces system y+L transport
activity with 4F2hc (the surface antigen 4F2 heavy chain) in oocytes.
Human y+LAT-1 is a new member of a family of polytopic
transmembrane proteins that are homologous to the yeast high affinity
methionine permease MUP1. Other members of this family, the
Xenopus laevis IU12 and the human KIAA0245 cDNAs, also
co-express amino acid transport activity with 4F2hc in oocytes, with
characteristics that are compatible with those of systems L and
y+L, respectively. y+LAT-1 protein forms a
rBAT and 4F2hc are homologous proteins that induce amino acid
transport in Xenopus oocytes (1, 2). These two proteins are
slightly hydrophobic, which prompted the hypothesis that rBAT and 4F2hc
are subunits or modulators of the corresponding amino acid transporter.
This has been supported by several indirect observations: (i) rBAT and
4F2hc are involved in the induction of several activities in
Xenopus oocytes (3-6); (ii) these two proteins can be
immunodetected or immunoprecipitated as complexes of ASUR4 (Y12716), an adrenal steroid up-regulated cDNA from
Xenopus laevis A6 cells (12) induces an L-type
amino acid transport activity when co-expressed with 4F2hc in
oocytes.1 When comparing the
amino acid sequence of ASUR4 to protein data bases, many highly
homologous eukaryotic and prokaryotic amino acid transporter-related
proteins are listed within the amino acids, polyamines, and choline
(APC) family of transporters. Among these, and with highest degree of
identity (between 38 and 82% when corresponding protein regions are
compared) to ASUR4, are found its counterpart in human, E16 (Q01650)
(13), and in rat, TA1 (Q63016) (14); a human cDNA, termed KIAA0245 (D87432) (15); five different Caenorhabditis elegans open reading frames deduced from genomic DNA sequence (Z68216, U50308, Z74042, U56963, and U70850) (16); and a Schistosoma mansoni
cDNA, SPRM1 (L25068). In the same list appeared a yeast high
affinity methionine permease, MUP1 (17) (U40316), and many other
prokaryotic amino acid permeases. ASUR4 showed low, although
significant, identity (between 26 and 31%) with the mammalian transporters for cationic amino acids
CAT12 and CAT2 (18, 19).
Human E16 was first identified from peripheral blood leukocytes and
related to lymphocyte activation (13). Rat TA1 was cloned later on the
basis of its differential expression between hepatoma cells and normal
liver (14). E16, TA1, and ASUR4 cDNA were first described as
proteins 241 amino acids long. The presence in the data base of a
thyroid hormone regulated X. laevis cDNA, termed IU12
(AF019906) (20), which was 507 amino acid long and practically
identical to ASUR4 (only one amino acid was different in the
corresponding protein region), suggested that the former three
cDNAs were indeed longer. Very recently, F. Verrey has submitted a
new ASUR4 cDNA GenBank entry (accession number Y12716), which also
has 507 amino acids. Although IU12 and the new entry of ASUR4 still
differ in four disperse amino acids, we can consider that both
sequences correspond to the same gene in Xenopus. We can now
assume that E16 and TA1 are actually longer proteins.
In this study, we have identified a new human member of this group of
amino acid permease-related proteins. This protein, which we have named
y+L amino acid transporter-1 (y+LAT-1) does not
induce transport of amino acids in oocytes when injected alone, but
y+L activity is co-expressed when it is injected with
4F2hc. We demonstrate here that it forms an heterodimer with 4F2hc
linked by disulfide bridges with residue cysteine 109 of human 4F2hc. Its pattern of expression and its chromosomal localization indicate that this gene could be responsible for lysinuric protein intolerance (21), an inherited disorder of cationic amino acid transport.
Oocytes, Injections, and Uptake Measurements--
Oocyte origin,
management, and injections were as described elsewhere (1, 2).
Defolliculated stage VI X. laevis oocytes were injected with
different amounts of human 4F2hc, human y+LAT-1, human
y+LAT-2 (KIAA0245), or X. laevis IU12 cRNA.
Amino acid transport rates obtained with oocytes injected with water
(50 nl) were similar to those of uninjected oocytes (data not shown).
Synthesis of human 4F2hc cRNA (22) was as described (11). IU12 was a
gift from Shi and co-workers (20), and the cRNA was obtained by cutting the cDNA, cloned in pBluescript SK PCR Amplification and Sequencing--
For PCR amplification,
first strand cDNA was synthesized from 5 µg of total RNA purified
from opossum kidney (23) cells using the SuperScript II kit (Life
Technologies, Inc.). Two degenerate forward and reverse primers were
designed based on two highly conserved regions among KIAA0245,
IU12, E16, TA1, and SPRM1 proteins. From region 1 sequence (A/S)REGHLP
(corresponding to residues 347-353 of KIAA0245), a forward
5'-C(C/T)(C/A)G(C/A/G)GA(G/A)GG(C/G)CA(C/T)CT(G/C/T/A)CC-3' primer
(1F) was synthesized, as well as a reverse (2R)
5'-A(T/G)G(A/C)(T/A)(A/G)-AA(C/G)A(C/A)(C/G)A(C/T)(T/A/G)GG-3' primer deduced from region 2 sequence P(I/V)(V/F)F(I/C)(I/L)
(corresponding to residues 429-434 of KIAA0245). Amplification was
carried out in a Perkin-Elmer 9600 thermocycler, and conditions were as
follows: hot start of 3 min at 94 °C; 15 cycles of denaturing
(94 °C for 25 s), annealing (starting 65-50 °C lowering
1 °C each cycle for 30 s), and extension (74 °C for 70 s); 25 cycles of denaturing (94 °C for 25 s), annealing
(50 °C for 30 s), and extension (74 °C for 70 s); and a
final extension of 4 min at 72 °C. PCR-amplified DNA fragments with
the expected length were subcloned into pGEM-T easy vector (Promega)
and sequenced in one direction. The DNA sequence obtained and all
frames of the deduced amino acid sequences were then compared with DNA
and protein sequence data bases. All sequences carried out in this work
were performed in one or both directions (in the case of clone 727811)
with D-Rhodamine Dye Terminator Cycle Sequencing Ready Reaction
(Perkin-Elmer). Analysis of the sequence reactions was done with an Abi
Prism 377 DNA sequencer.
Computer Analysis--
Amino acid or nucleotide sequence
homology searching was performed using basic local alignment tool
(BLAST) via on-line connection to the National Center of Biotechnology
Information. The programs BLASTn, BLASTp, and BLASTx were run using
default parameters. Data base searching was done against nonredundant
or dbEST, when searching for nucleotide sequence homology, and
versus nonredundant when comparing to peptide sequences. The
clusters of Expressed Sequence Tag were identified and analyzed with
the IMAGE data base and Telethon Institute of Genetics and Medicine EST
assembly machine tool. Multiple nucleotide or amino acid sequence
comparisons were done with CRUSTALW via on-line connection to the
Genome World Wide Web server (University of Tokyo) and to the Baylor
College of Medicine Search Launcher (University of Texas). Amino acid sequence deduction and other sequence analysis were done with Genetics
Computer Group utilities.
The prediction of transmembrane segments of the proteins
y+LAT-1, y+LAT-2, IU12, and SPRM1 was
established on the basis of the combination of three criteria: (i) the
prediction of transmembrane segments by the programs of Aloy et
al. (23) and TopPred II (24) using the algorithms of G. von Heijne
(25), Goldman, Engelman, and Steitz (26), and KD
(27) to determine the position of hydrophobicity peaks; (ii) the
prediction of Northern Blot Analysis--
A human adult poly(A+)
membrane containing 12 different tissues, purchased from
CLONTECH (Palo Alto, CA) was used. Insert of clone
727811 was separated from the pT7T3D-727811 vector with ApaI-NotI digestion. This 2250-bp-long DNA
fragment was purified, labeled with [ Chromosome Mapping--
Chromosome mapping was done using the
Stanford Human Genome Center G3 Radiation Hybrid panel (medium
resolution). DNA samples of this panel, along with total genomic DNA
and pT7T3-727811 (used as a positive controls), were PCR-screened for
the presence of the genomic sequences flanked by the primers F7
(5'-GGAAGTTGAAAAGGAAAGC-3') and R7 (5'-AAGGAGACAGGAAATTGG-3'),
which are located at the 3'-untranslated region of the cDNA.
PCR amplifications were carried out in a Perkin-Elmer 9600 thermocycler, using 200 µM dNTP, 3 pmol of each primer
and DNA Taq polymerase (Boehringer Mannheim) in PCR buffer.
Amplification conditions were as follows: 35 cycles of denaturing
(94 °C for 30 s), annealing (56 °C for 40 s), and
extension (74 °C for 30 s). PCR results were classified as 0 (for no amplification), 1 (for positive amplification), or r (for
uncertain) and submitted to the Radiation Hybrid Mapping E-mail server
at the Stanford Human Genome Center (SHGC). Resulting chromosomal
location, referred to a SHGC marker, was obtained automatically via
E-mail from this server.
Site-directed Mutagenesis--
Construction of the mutants C109S
and C330S of human 4F2hc was as described in Ref. 11.
Immunoprecipitation of Methionine-labeled Proteins from Xenopus
Oocytes--
Oocytes were injected with 10 ng of human 4F2hc or C109S
human 4F2hc (CS1) or C330S human 4F2hc (CS2) alone or in combination with 10 ng of y+LAT-1 cRNA. After 24 h,
[35S]methionine (0.5 µCi in 50 nl of water; ICN) was
injected, and the oocytes (usually 20 oocytes) were incubated for
48 h at 18 °C in 1 ml of modified Barth's solution. Oocytes
were then harvested and lysed in a buffer containing 50 mM
Tris-HCl, pH 8.0, 120 mM NaCl, 0.5% Nonidet P-40, and 1 mM phenylmethanesulfonyl fluoride. Extracts were
centrifuged twice at 1000 × g in order to remove the
yolk granules. Aliquots of 106 cpm were rotated overnight
at 4 °C with 20 µl of human 4F2hc antibody (Immunotech, Marseille,
France) previously bound to protein G-Sepharose (Sigma). The beads were
washed five times in a buffer containing 20 mM Tris-HCl, pH
8.0, 100 mM NaCl, 1 mM EDTA, 500 mM
LiCl, and 0.5% Nonidet P-40 and five times in the same buffer without
LiCl. The resulting immunoprecipitates were heated in sample buffer
with or without 100 mM dithiothreitol for 5 min at 95 °C
before gel loading. The labeled proteins were separated by
SDS-polyacrylamide gel electrophoresis and visualized by
autoradiography after enhancement with 1 M sodium salicylate.
Our goal was to identify any new member of the amino acid
transporter-related family expressed in kidney and potentially involved in reabsorption of amino acids. For this purpose reverse transcription PCR amplification of total RNA from opossum kidney cells (32) was
performed. Degenerated primers were designed on the basis of two highly
conserved protein regions (see under "Experimental Procedures")
revealed after a multiple amino acid sequence comparison among
KIAA0245, E16, TA1, IU12, and SPRM1 proteins. Electrophoretic analysis
of the PCR showed one band of 228 bp, which was subcloned into
pGEMT-easy vector and amplified in Escherichia coli. Several clones were then analyzed by sequencing. Nucleotide sequence of clone
b4c2 showed a significant degree of identity to the amino acid
transporter-related proteins when compared, using BLASTx program, to
nonredundant peptide data bases. Deduced amino acid sequence comparison
showed an identity of 75, 52, 49, 47, and 20% for b4c2 with KIAA0245,
IU12, TA1, E16, and SPRM1, respectively. This high degree of identity
with KIAA0245 suggested that we had cloned a fragment of the KIAA0245
ortholog cDNA in opossum. To rule out the presence of other human
genes having high homology to KIAA0245, the coding region sequence of
this gene was run as a query with BLASTn program against dbEST data
bases. Flanking 3'- and 5'-untranslated regions were avoided to
minimize the presence of KIAA0245 EST in the results. We identified an
IMAGE EST cluster (46303) that corresponds to a new unidentified human
gene with a high degree of identity (75%) to KIAA0245. EST AA393488
(located 5' of this cluster) and EST AA400789 (located 3' of this
cluster and presenting a poly(A+) tail) are flanking
regions of IMAGE cDNA clone 727811 and comprised the whole
cDNA. We named this clone y+LAT-1 (y+L
amino acid transporter), and KIAA0245 tentatively as a
y+LAT-2 because they yielded system y+L amino
acid transport activity when co-injected with 4F2hc in oocytes (see below).
Two direction sequencing of clone 727811 (Fig.
1) showed a cDNA 2245 bp long.
Sequence comparison of the corresponding region of y+LAT-1
with the opossum b4c2 clone revealed 82 and 81% identity for DNA and
protein, respectively. We then assumed that b4c2 clone is a fragment of
the corresponding y+LAT-1 in opossum. The size of the human
y+LAT-1 cDNA corresponds to the transcript seen in
Northern blots (see Fig. 5). The first ATG codon lies within a good
consensus initiation sequence (5'-CCACC) (33). The open reading frame continues to the first stop codon (TAA) at base 1820 and codes for a
protein of 511 amino acid residues with a predicted molecular mass of
55,988 Da. The nucleotide sequence of y+LAT-1 has been
deposited in the GenBank data base (accession number: AF092032).
Hydrophobicity studies (see under "Experimental Procedures") show
12 transmembrane domains with both C- and N-terminal segments intracytoplasmatic, a typical protein structure similar to some previously reported organic solute transporters (34-36). There is only
one putative N-glycosylation site underlined in Fig. 1 (Asn-Ala-Ser)
between the putative transmembrane segments VIII and IX. In our
prediction model, this segment is cytoplasmic and cannot be
glycosylated. There are also two putative casein kinase II
phosphorylation sites (threonine 8 and serine 11, located in the
putative cytoplasmic N-terminal segment) and one putative protein
kinase C phosphorylation site (threonine 96, located intracellularly between the putative transmembrane segments II and III). A multiple sequence alignment of the predicted amino acid sequence of
y+LAT-1, y+LAT-2 (KIAA0245), IU12, E16, and
SPRM1 is shown in Fig. 2. The percentages
of identity between y+LAT-1 and y+LAT-2, E16,
IU12, SPRM1, and the yeast permease MUP1 are 75, 51, 53, 39, and 31%,
respectively. The predicted structural model of these proteins is also
very similar. Only the consensus for the position of the transmembrane
segment III can vary for the proteins presented in Fig. 2. For
y+LAT-1 and y+LAT-2, this segment could be
located in the position indicated in Fig. 2. However, in the case of
IU12, the fragment is displaced 10 amino acids to the C-terminal end,
and in the protein SPRM1, the fragment is moved 5 amino acids to the
N-terminal end. Because 4F2hc is associated with y+LAT-1 in
a disulfide bond-dependent manner (see Fig. 7), we looked for cysteine residues conserved in these proteins. There are only two
cysteines conserved in all these proteins: cysteine 151 of y+LAT-1, located extracellularly in our structure model
prediction, corresponding to residues 159, 164, and 137 of
y+LAT-2, IU12, and SPRM1, respectively; and cysteine 174, located in the transmembrane domain IV and corresponding to residues
182, 187, and 160 of y+LAT-2, IU12, and SPRM1,
respectively. These two cysteines are not conserved in the yeast
permease MUP1.
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*
§,¶,
,
Departament de Fisiologia (Immunologia), Facultat de
Biologia, Universitat de Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain and the ** Laboratory of Molecular Embryology
NICHD, National Institutes of Health, Bethesda,
Maryland 20892-5431
ABSTRACT
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Abstract
Introduction
Procedures
Results
Discussion
References
135-kDa, disulfide bond-dependent heterodimer with 4F2hc
in oocytes, which upon reduction results in two protein bands of 85
kDa (i.e. 4F2hc) and 40 kDa (y+LAT-1).
Mutation of the human 4F2hc residue cysteine 109 (Cys-109) to serine
abolishes the formation of this heterodimer and drastically reduces the
co-expressed transport activity. These data suggest that
y+LAT-1 and other members of this family are different 4F2
light chain subunits, which associated with 4F2hc, constitute different amino acid transporters. Human y+LAT-1 mRNA is
expressed in kidney 
peripheral blood leukocytes lung > placenta = spleen > small intestine. The human
y+LAT-1 gene localizes at chromosome 14q11.2
(17cR 374 kb from D14S1350), within the lysinuric protein
intolerance (LPI) locus (Lauteala, T., Sistonen, P., Savontaus, M. L., Mykkanen, J., Simell, J., Lukkarinen, M., Simmell, O., and Aula, P. (1997) Am. J. Hum. Genet. 60, 1479-1486). LPI is an
inherited autosomal disease characterized by a defective dibasic amino
acid transport in kidney, intestine, and other tissues. The pattern of
expression of human y+LAT-1, its co-expressed transport
activity with 4F2hc, and its chromosomal location within the LPI locus,
suggest y+LAT-1 as a candidate gene for LPI.
INTRODUCTION
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Abstract
Introduction
Procedures
Results
Discussion
References
125 kDa in the
absence of reducing agents and as two proteins of 85 kDa (4F2hc or
rBAT) and 40 kDa in the presence of reducing agents (7-9); and
(iii) in oocytes, there is a dissociation between the expression of
4F2hc and rBAT at the plasma membrane and the induction of system
y+L and b0,+ activity, respectively, indicating
that this expression is limited by an endogenous factor (10, 11). We
have recently provided new evidence that the amino acid transport
system y+L has a heterodimeric structure (11). Thus, we
have shown that the y+L activity induced in oocytes by a
cysteine-less mutant of human 4F2hc is also inactivated by
membrane-impermeant thiol-specific reagents, implying that another
protein is required for this function, which would have external
cysteine(s) that are targets of these reagents. Moreover, the
sensitivity to inactivation is increased by reducing conditions and in
4F2hc mutants in which cysteine 109 has been mutated. These results
indicate that Cys-109 may be linked by a disulfide bond to the cysteine
target of these agents of the associated protein.
EXPERIMENTAL PROCEDURES
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Abstract
Introduction
Procedures
Results
Discussion
References
between the sites
XhoI and EcoRI with ApaI and using T3
polymerase. The open reading frame of y+LAT-1 was obtained
from the Integrated and Molecular Analysis of Genomes and their
Expression (IMAGE) cDNA clone 727811 cloned in the vector pT7T3
between the restriction sites EcoRI and NotI. To
obtain the y+LAT-2 cRNA, because it has a long
3'-untranslated region and is not expressed properly in
Xenopus oocytes, we inserted the open reading frame of
KIAA0245 (obtained from Takahiro Nagase from the Kasuza DNA Research
Institute, (15) and cloned in pBluescript II SK+) in
another vector with a shorter 3' tail. Subcloning was done by cutting
pBluescript-KIAA0245 with ApaI and filling with Klenow; the
clone was then ethanol-precipitated, cut again with PstI, and finally ligated into pSPORT1-human rBAT that had been cut with
PstI and Bst1107I. Influx rates of
L-[3H]arginine,
L-[3H]leucine were measured in 100 mM NaCl or 100 mM choline Cl medium at the
indicated days after injection and under linear conditions. When
presented, the induced uptake was calculated by subtracting uptake
values in uninjected oocytes from those of the corresponding cRNA-injected oocytes.
-helix in the predicted secondary structure using a
program that combines the algorithms of Chou-Fasman and Rose (28); and
(iii) the surface probability and flexibility index plots, according to
the algorithms of Boger (29) and Karplus and Schulz (30), respectively.
-32P]dCTP
(Amersham) using a random oligonucleotide-priming labeling kit
(Amersham), and used as a probe. Hybridization, carried out in Express
HybTM Hybridization solution (CLONTECH), and wash
conditions were as recommended by the manufacturer. To rule out
differences in sample loading, the CLONTECH
membrane was hybridized with human 
-actin probe. A nonradioactive
fluorescein and anti-fluorescein peroxidase-conjugated antibody
detection kit was used (Amersham). Hybridization, washes, and detection
conditions were as suggested by the supplier.
RESULTS
Top
Abstract
Introduction
Procedures
Results
Discussion
References
View larger version (67K):
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Fig. 1.
Nucleotide and deduced amino acid sequence of
the y+LAT-1 cDNA. The size of the clone
is 2245 bp and it contains a 5'-untranslated region of 268 bp, followed
by an open reading frame of 511 amino acids and a 3'-untranslated
region of 423 bp that contains a poly(A) tail of 38 bp. The stop codon
(TAA) is indicated by one star. The possible polyadenylation
signal is underlined. The putative transmembrane domains,
deduced by hydrophobicity analysis (see under "Experimental
Procedures"), are shown in boldface.
View larger version (94K):
[in a new window]
Fig. 2.
Amino acid sequence comparison of five
members of the family of amino acid transporter-related proteins.
Multialignment was done using the program CLUSTALW Sequence Alignment
from Baylor College of Medicine. The thin horizontal lines
indicate the putative 12 transmembrane domains determined by computer
analysis (see under "Experimental Procedures"). The amino acid
residues identical to y+LAT-1 sequence are indicated by
gray boxes. The solid frame box indicates a
potential N-glycosylation site, but according to our membrane topology
prediction, this site is intracellular and cannot be glycosylated. Two
cysteine residues conserved in all the proteins presented here are
indicated by a star.
The human y+LAT-1 gene was chromosome mapped by
using a radiation hybrid panel (see under "Experimental
Procedures") with primers corresponding to the 3'-untranslated region
of the y+LAT-1 cDNA. From this screening, we obtained
13 positive, 70 negative and 2 uncertain results. Chromosome mapping
results, obtained from the SGHC server, linked
y+LAT-1, with a logarithm odds score of 10.4, to
a distance of 17 cR (374 kb) from the marker SHGC-13532 (D14S1350)
located at chromosome 14q11.2. When uncertain samples were submitted as
positive, the localization was linked to the T-cell receptor chain
marker, which lies 150 kb telomeric of SHGC-13532.
cRNA from y+LAT-1, y+LAT-2, and IU12 was prepared and injected into oocytes alone or in combination with an equimolar quantity of human 4F2hc cRNA and tested for transport of arginine and leucine (50 µM) in the presence or in the absence (choline) of sodium (100 mM) (Fig. 3). These three proteins do not induce any amino acid transport activity when injected alone, but interestingly, they induce different activities when co-injected with 4F2hc. In the case of y+LAT-1 and y+LAT-2 (KIAA0245), the pattern of induced activity resembles that described as system y+L (37) (i.e. sodium-independent uptake of dibasic amino acids and sodium-dependent uptake of some neutral amino acids). IU12, by contrast, induced an activity above that of 4F2hc alone, which is compatible with the activity described as system L (i.e. sodium-independent uptake of neutral amino acids). For y+LAT-1, the induced activity is very similar to the component of y+L activity induced by 4F2hc alone, but the level of induction is higher. From 10 independent experiments, the average fold induction relative to the induction of 4F2hc alone was 3.8 ± 0.9 (range, 2-14-fold). To explain this increase, we performed kinetic analysis, and from an individual experiment, the kinetic parameters showed an increase in Vmax without apparent change in the K0.5 parameter (4F2hc-induced uptake: K0.5, 55 ± 15 µM; Vmax, 18 ± 4 pmol of arginine (choline medium)/15 min per oocyte; 4F2hc plus y+LAT-1-induced uptake: K0.5, 45 ± 18 µM; Vmax, 36 ± 5 pmol of arginine (choline medium)/15 min per oocyte). A further characterization of this transport activity co-expressed by y+LAT-1 and y+LAT-2 is in progress.3
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, open bars) of 100 mM NaCl was determined
for 5 min. Amino acid uptake (pmol/oocyte × 5 min) was calculated
by subtracting the uptake in uninjected from that of the cRNA injected
groups. Amino acid uptake in uninjected oocytes was as follows: (i)
L-[3H]arginine uptake: 1.1 ± 0.2 (choline medium) and 3.5 ± 0.5 (sodium medium); (ii)
L-[3H]leucine uptake: 3.1 ± 0.6 (choline medium) and 3.8 ± 0.4 (sodium medium).
To further characterize the uptake activity co-expressed by y+LAT-1 and 4F2hc, we measured the inhibition of arginine uptake by different amino acids at a 100-fold excess concentration (5 mM). As shown in Table I, dibasic amino acids inhibit 50 µM arginine uptake in a sodium-independent manner, but in contrast, neutral amino acids inhibit more in the presence of sodium. In order to define better the effect of sodium on the inhibition by neutral amino acids, the uptake of L-arginine (50 µM) was measured in the presence or absence of sodium and in the presence of different concentrations of L-leucine (Fig. 4). These results showed clearly that sodium increased the affinity of L-leucine. This effect is indistinguishable in 4F2hc alone or 4F2hc plus y+LAT-1-injected oocytes. All of this is consistent with the expression of y+L transport activity (38).
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The tissue expression of the mRNA corresponding to
y+LAT-1 was examined by Northern blot analysis at high
stringency conditions (Fig. 5). The
mRNA species of 2.4 kb hybridizes with the y+LAT-1
cDNA. Transcript expression is as follows: kidney peripheral blood leukocytes lung > placenta = spleen > small intestine.
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Recently (11), we have postulated that residue cysteine 109 of human 4F2hc could be involved in the formation of a disulfide bond with a putative membrane protein already present in the Xenopus oocyte to express system y+L transport activity. To test whether this is also the case with human y+LAT-1 protein, we performed co-injection experiments with C109S (CS1) or C330S (CS2) human 4F2hc mutants (Fig. 6). The CS1 mutant injected alone led to a decrease of 56% in the induced activity compared with the wild type. This agrees with previous results (11) that showed a Vmax decrease of 50% without changes in the K0.5 parameter for this mutant. Moreover, CS1 co-injected with y+LAT-1 showed a 74% decrease in transport expression compared with wild type 4F2hc co-injected with y+LAT-1. In contrast, the CS2 4F2hc mutant showed no decrease in the induced activity when injected alone (similar to previous results; Ref. 11) or co-injected with y+LAT-1.
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In the batch of oocytes used in the experiment shown in Fig. 6, we
checked whether y+LAT-1 and 4F2hc proteins could form a
heterodimeric structure via a disulfide bond. This was done by
[35S]methionine labeling and immunoprecipitation using a
monoclonal antibody directed to human 4F2hc (Fig.
7). Under nonreducing conditions, two
4F2hc-specific protein bands were detected in 4F2hc-injected oocytes
with 85- and 169-kDa electrophoretic mobilities. A band of 110
kDa was also visible, but it did not correspond to 4F2hc because it was
also detected after immunoprecipitation of extracts from oocytes
co-expressing 4F2hc and y+LAT-1 with protein G-Sepharose
without 4F2hc antibody. The 85-kDa band corresponds to 4F2hc, as
detected in activated lymphocytes (9). This band is also detected in
oocytes not injected with 4F2hc cRNA, suggesting that
Xenopus oocytes express a homologous 4F2hc protein. The
169-kDa band is not visible in reducing conditions or in oocytes
expressing CS1 4F2hc, suggesting that this band might represent 4F2hc
homodimers linked by a disulfide bridge involving cysteine residue 109. In oocytes co-injected with wild type or CS2 4F2hc plus
y+LAT-1, a new 4F2hc-specific band of 135 kDa appears.
Under reducing conditions, this band is drastically reduced and a new
y+LAT-1-specific 40-kDa band appears (Fig. 7). In
contrast, neither the 135- nor the 40-kDa band is visible, even after
very long film exposures, in oocytes co-injected with CS1 4F2hc and
y+LAT-1. This indicates that the 135-kDa band corresponds
to a heterodimer of 4F2hc and y+LAT-1, linked by a
disulfide bridge involving cysteine 109 of 4F2hc. The 135-kDa band is
also visible after very long film exposures in 4F2hc-injected oocytes
and might represent the association of 4F2hc with a Xenopus
y+LAT-1 homologous protein (data not shown). It is worth
mentioning that this band is the only one that correlates with the
induced y+L transport activity (see Figs. 6 and 7).
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DISCUSSION |
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Introduction
Procedures
Results
Discussion
References
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In this study, we have identified a new member (y+LAT-1) of a family of amino acid transporter-related proteins also composed in humans by y+LAT-2 (KIAA0245) and E16. We have characterized the human y+LAT-1 cDNA sequence, chromosomal location, and pattern of expression of its mRNA and demonstrated that when co-expressed with 4F2hc, it yields y+L amino acid transport activity and forms a disulfide bond-dependent complex with 4F2hc through residue Cys-109 in oocytes. Therefore, y+LAT-1 is a putative light subunit of the surface antigen 4F2hc. Moreover, we also present human y+LAT-1 as a strong candidate for the lysinuric protein intolerance (LPI) gene.
The surface antigen 4F2 from lymphocytes has been previously
immunoprecipitated as a complex of 125 kDa, which upon reduction resulted in two protein bands of 85 kDa (the heavy chain of 4F2 surface
antigen, or 4F2hc) and an unidentified light chain with an
electrophoretic mobility of 40 kDa; this light chain is known to be
nonglycosylated and very hydrophobic (9, 39). We have recently
demonstrated that system y+L transport activity induced by
4F2hc in oocytes requires association, most probably by disulfide
bridges, with a plasma membrane endogenous protein (11). Here we
demonstrated that human y+LAT-1 and 4F2hc combine to
generate system y+L amino acid transport activity in
oocytes and form a heterodimeric complex of 135 kDa. Moreover, this
complex correlates with the induction of y+L transport
activity by 4F2hc and y+LAT-1 co-expression in oocytes.
Interestingly, immunoprecipitation of the 135-kDa complex and
subsequent reduction results in the appearance of a
y+LAT-1-specific 40-kDa protein band. All of this
strongly indicates that human y+LAT-1 is a light chain of
the surface antigen 4F2hc.
Three proteins, y+LAT-1 and y+LAT-2 (present study) and IU12 (present study, and for the equivalent protein ASUR4 or the human ortholog E16)2 induce with 4F2hc several amino acid transport activities in oocytes: system y+L activity for y+LAT-1 and y+LAT-2, or system L-type for IU12 or E16. This suggests that at least these three proteins (human y+LAT-1, y+LAT-2, and E16) might be light subunits of 4F2hc with associated amino acid transport activities. This is in full agreement with the fact that both y+L and L transport activities have been associated with the expression of 4F2hc cRNA or 4F2hc-containing mRNA (2, 40-42, 5-6, 43). Interestingly, y+LAT-1 is expressed in tissues where mRNA-induced y+L activity has been reported (small intestine, placenta and lung) (41, 42).4 The final demonstration that y+LAT-1, y+LAT-2, and E16 are light subunits of the surface antigen 4F2 awaits co-immunoprecipitation studies from tissue or cell samples.
Our data strongly suggest that the 4F2hc and y+LAT-1
heterodimeric complex is linked by a disulfide bridge involving 4F2hc residue cysteine 109. Thus, both 4F2hc-induced (present study and Ref.
11) and 4F2hc/y+LAT-1-induced system y+L
transport activity is drastically reduced when the 4F2hc residue cysteine 109 is mutated to serine. In parallel to this, the formation of the 4F2hc/y+LAT-1 heterodimer is abolished by this
mutation. This suggests that C109S 4F2hc mutant is able to form an
active transporter heterodimer with y+LAT-1, albeit with
lower efficiency than wild type 4F2hc. Most probably, weak
protein-protein interactions between C109S 4F2hc and
y+LAT-1 are destabilized during detergent solubilization
prior to immunoprecipitation. In favor of this, the 4F2hc-induced
y+L transport activity is not sensitive to
-mercaptoethanol treatment, even though this increases sensitivity
to inactivation by cysteine-specific reagents (11). Two cysteine
residues of y+LAT-1 (residues 151 and 174) are conserved
among the known full-length protein members of this family.
Site-directed mutagenesis studies are currently in progress to identify
the y+LAT-1 residue involved in the disulfide bridge with
the Cys-109 residue of 4F2hc.
One intriguing question is why y+LAT-1 does not induce
amino acid transport when injected alone in oocytes and why 4F2hc does. One possible explanation is that the exogenous 4F2hc may constitute a
functional y+L transporter with a homologous protein of the
y+LAT-1 family already present in the oocyte. The oocyte
would synthesize more y+LAT-1-like subunits than 4F2hc-like
subunits. This would be similar to the activation of the oocyte
catalytic subunit of the Na+/K+ ATPase by
expression of foreign subunits (44). By analogy to
Na+/K+ ATPase (45, 46), the oocyte
y+LAT-1-like subunits might be present in the endoplasmic
reticulum and would be transported to the plasma membrane when
exogenous 4F2hc is added. In this sense, the y+L activity
is already present in the Xenopus oocyte (2), and we can
visualize an immunoprecipitated 4F2hc antibody protein with the same
molecular weight as 4F2hc in uninjected oocytes (Fig. 7).
Structural and functional evidence suggested that rBAT also associates with an oocyte plasma membrane protein to express system bo,+-like amino acid transport activity (see under "Introduction," and see Refs. 47 and 48 for recent reviews). Therefore, it will be interesting to determine whether some of the members of the transporter-related family can also interact with the rBAT protein. Preliminary results5 indicate that y+LAT-1, y+LAT-2, and IU12 do not cause bo,+-like amino acid transport activity with rBAT in oocytes.
LPI is an autosomal recessive disease in which transport of the
cationic amino acids lysine, arginine, and ornithine is defective. This
defect has been localized at the basolateral membranes of epithelial
cells in small intestine (49, 50) and in the renal tubules (51). Simell
and co-workers (52) reported that LPI fibroblast showed a reduced
trans-stimulated efflux of cationic amino acids. Clinical
signs of LPI include hyperammonemia and episodes of stupor,
immunological abnormalities (53), growth retardation, and muscle
hypotonia. Potentially fatal interstitial lung disease and progressive
renal failure may occur at any age (54). Recently, Lauteala et
al. (55) have assigned, through linkage analysis of 20 Finnish LPI
families, the LPI gene locus to the proximal long arm of chromosome 14. In this work, recombination studies placed the locus between markers
D14S72 and MYH7; the phenotype showed the highest linkage
desequilibrium with marker T-cell receptor chain within this locus.
Although functional criteria pointed to the cationic amino acid
transporters (hCAT-1 and hCAT-2) as candidate genes, linkage studies,
using flanking microsatellite markers, excluded both as the mutated
gene in LPI (56). The human y+LAT-1 gene is a
good candidate for LPI: (i) 4F2hc is expressed at the basolateral
membrane of proximal tubule epithelial cells in the kidney (57). (ii)
The y+L activity induced by 4F2hc in oocytes is an
exchanger activity that mediates the efflux of cationic amino acids and
the influx of neutral amino acids plus sodium (58). This would explain why the efflux and not the influx (because of the presence of a member
of the CAT family of transporters) is affected. (iii) The expression
pattern of this gene is consistent with the tissues in which some
defect in LPI has been detected (lung, immune system cells, kidney, and
intestine). (iv) Finally, its chromosomal localization is within the
locus of the LPI gene (55). Mutational analysis to prove this
hypothesis is currently in progress.
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ACKNOWLEDGEMENTS |
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We thank Belen Peral for helping and making possible the radiation hybrid analysis and Núria Reig for helping in reviewing the manuscript. We also thank Robin Rycroft for editorial help.
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Note Added in Proof |
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After this paper was accepted for publication the observations by Verrey and co-workers were published (Mastroberardino, L. Spindler, B., Pfeiffer, R., Skelly, P. J., Loffing, J., Shoemaker, C. B., and Verrey, F. (1998) Nature 395, 288-291).
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FOOTNOTES |
|---|
* This research was supported in part by EU BIOMED 2 Grant PL963514, Dirección General de Investigación Científica y Técnica Research Grants PM96/0060, and Generalitat de Catalunya (Spain) Grant 1997 SGR 121.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF092032.
These two authors contributed equally to this work.
§ Recipients of a grant from the Ministerio de Educación y Cultura.
¶ Recipients of a grant from the Comissió Interdepartamental de Recerca i Tecnologia.
To whom correspondence should be addressed. Tel.:
34-93-4021543; Fax: 34-93-4021559.
The abbreviations used are: CAT, cationic amino acid transporter; LAT, L amino acid transporter; LPI, lysinuric protein intolerance; IMAGE, Integrated and Molecular Analysis of Genomes and their Expression; SHGC, Stanford Human Genome Center; PCR, polymerase chain reaction; bp, base pair(s).
1 F. Verrey, personal communication.
3 M. Pineda, R. Estévez, and M. Palacín, manuscript in preparation.
4 R. Estévez and M. Palacín, unpublished results.
5 M. Pineda, D. Torrents, and M. Palacín, unpublished observations.
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 S. Kaneko, A. Ando, E. Okuda-Ashitaka, M. Maeda, K. Furuta, M. Suzuki, M. Matsumura, and S. Ito Ornithine Transport Via Cationic Amino Acid Transporter-1 Is Involved in Ornithine Cytotoxicity in Retinal Pigment Epithelial Cells Invest. Ophthalmol. Vis. Sci., January 1, 2007; 48(1): 464 - 471. [Abstract] [Full Text] [PDF]
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L. Martin, M. Comalada, L. Marti, E. I. Closs, C. L. MacLeod, R. Martin del Rio, A. Zorzano, M. Modolell, A. Celada, M. Palacin, et al. Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages Am J Physiol Cell Physiol, May 1, 2006; 290(5): C1364 - C1372. [Abstract] [Full Text] [PDF]
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M. Desforges, H. A. Lacey, J. D. Glazier, S. L. Greenwood, K. J. Mynett, P. F. Speake, and C. P. Sibley SNAT4 isoform of system A amino acid transporter is expressed in human placenta Am J Physiol Cell Physiol, January 1, 2006; 290(1): C305 - C312. [Abstract] [Full Text] [PDF]
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E. Fernandez, D. Torrents, A. Zorzano, M. Palacin, and J. Chillaron Identification and Functional Characterization of a Novel Low Affinity Aromatic-preferring Amino Acid Transporter (arpAT): ONE OF THE FEW PROTEINS SILENCED DURING PRIMATE EVOLUTION J. Biol. Chem., May 13, 2005; 280(19): 19364 - 19372. [Abstract] [Full Text] [PDF]
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 M. Palacin, V. Nunes, M. Font-Llitjos, M. Jimenez-Vidal, J. Fort, E. Gasol, M. Pineda, L. Feliubadalo, J. Chillaron, and A. Zorzano The Genetics of Heteromeric Amino Acid Transporters Physiology, April 1, 2005; 20(2): 112 - 124. [Abstract] [Full Text] [PDF]
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S. Bodoy, L. Martin, A. Zorzano, M. Palacin, R. Estevez, and J. Bertran Identification of LAT4, a Novel Amino Acid Transporter with System L Activity J. Biol. Chem., March 25, 2005; 280(12): 12002 - 12011. [Abstract] [Full Text] [PDF]
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T. Verri, C. Dimitri, S. Treglia, F. Storelli, S. De Micheli, L. Ulianich, P. Vito, S. Marsigliante, C. Storelli, and B. Di Jeso Multiple pathways for cationic amino acid transport in rat thyroid epithelial cell line PC Cl3 Am J Physiol Cell Physiol, February 1, 2005; 288(2): C290 - C303. [Abstract] [Full Text] [PDF]
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 O. Teijido, A. Martinez, M. Pusch, A. Zorzano, E. Soriano, J. A. del Rio, M. Palacin, and R. Estevez Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts Hum. Mol. Genet., November 1, 2004; 13(21): 2581 - 2594. [Abstract] [Full Text] [PDF]
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P. M. Martin, A. E. Sutherland, and L. J. Van Winkle Amino Acid Transport Regulates Blastocyst Implantation Biol Reprod, October 1, 2003; 69(4): 1101 - 1108. [Abstract] [Full Text] [PDF]
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B. Jain-Vakkalagadda, S. Dey, D. Pal, and A. K. Mitra Identification and Functional Characterization of a Na+-Independent Large Neutral Amino Acid Transporter, LAT1, in Human and Rabbit Cornea Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2919 - 2927. [Abstract] [Full Text] [PDF]
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 J. W. A. Ritchie, Y.-B. Shi, Y. Hayashi, F. E. Baird, R. W. Muchekehu, G. R. Christie, and P. M. Taylor A Role for Thyroid Hormone Transporters in Transcriptional Regulation by Thyroid Hormone Receptors Mol. Endocrinol., April 1, 2003; 17(4): 653 - 661. [Abstract] [Full Text] [PDF]
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 E. Fernandez, D. Torrents, J. Chillaron, R. Martin del Rio, A. Zorzano, and M. Palacin Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK J. Am. Soc. Nephrol., April 1, 2003; 14(4): 837 - 847. [Abstract] [Full Text] [PDF]
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G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]
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 T. Uinuk-ool, W. E. Mayer, A. Sato, R. Dongak, M. D. Cooper, and J. Klein Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes PNAS, October 29, 2002; 99(22): 14356 - 14361. [Abstract] [Full Text] [PDF]
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 H. Sato, M. Tamba, S. Okuno, K. Sato, K. Keino-Masu, M. Masu, and S. Bannai Distribution of Cystine/Glutamate Exchange Transporter, System xc-, in the Mouse Brain J. Neurosci., September 15, 2002; 22(18): 8028 - 8033. [Abstract] [Full Text] [PDF]
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E. Fernandez, M. Carrascal, F. Rousaud, J. Abian, A. Zorzano, M. Palacin, and J. Chillaron rBAT-b0,+AT heterodimer is the main apical reabsorption system for cystine in the kidney Am J Physiol Renal Physiol, September 1, 2002; 283(3): F540 - F548. [Abstract] [Full Text] [PDF]
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H. Matsuo, Y. Kanai, J. Y. Kim, A. Chairoungdua, D. K. Kim, J. Inatomi, Y. Shigeta, H. Ishimine, S. Chaekuntode, K. Tachampa, et al. Identification of a Novel Na+-independent Acidic Amino Acid Transporter with Structural Similarity to the Member of a Heterodimeric Amino Acid Transporter Family Associated with Unknown Heavy Chains J. Biol. Chem., May 31, 2002; 277(23): 21017 - 21026. [Abstract] [Full Text] [PDF]
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 M. Kakoki, W. Wang, and D. L. Mattson Cationic Amino Acid Transport in the Renal Medulla and Blood Pressure Regulation Hypertension, February 1, 2002; 39(2): 287 - 292. [Abstract] [Full Text] [PDF]
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Y. Okamoto, M. Sakata, K. Ogura, T. Yamamoto, M. Yamaguchi, K. Tasaka, H. Kurachi, M. Tsurudome, and Y. Murata Expression and regulation of 4F2hc and hLAT1 in human trophoblasts Am J Physiol Cell Physiol, January 1, 2002; 282(1): C196 - C204. [Abstract] [Full Text] [PDF]
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J. Chillaron, R. Roca, A. Valencia, A. Zorzano, and M. Palacin Heteromeric amino acid transporters: biochemistry, genetics, and physiology Am J Physiol Renal Physiol, December 1, 2001; 281(6): F995 - F1018. [Abstract] [Full Text] [PDF]
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C. A. Wagner, F. Lang, and S. Broer Function and structure of heterodimeric amino acid transporters Am J Physiol Cell Physiol, October 1, 2001; 281(4): C1077 - C1093. [Abstract] [Full Text] [PDF]
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 B. P. Bode Recent Molecular Advances in Mammalian Glutamine Transport J. Nutr., September 1, 2001; 131(9): 2475S - 2485. [Abstract] [Full Text] [PDF]
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 G. Hennemann, R. Docter, E. C. H. Friesema, M. de Jong, E. P. Krenning, and T. J. Visser Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability Endocr. Rev., August 1, 2001; 22(4): 451 - 476. [Abstract] [Full Text] [PDF]
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 M. Papetti and I. M. Herman Controlling Tumor-Derived and Vascular Endothelial Cell Growth : Role of the 4F2 Cell Surface Antigen Am. J. Pathol., July 1, 2001; 159(1): 165 - 178. [Abstract] [Full Text] [PDF]
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 A.C. Mendes Ribeiro, T.M.C. Brunini, J.C. Ellory, and G.E. Mann Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure Cardiovasc Res, March 1, 2001; 49(4): 697 - 712. [Abstract] [Full Text] [PDF]
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M. Font, L. Feliubadalo, X. Estivill, V. Nunes, E. Golomb, Y. Kreiss, E. Pras, L. Bisceglia, A. P. d'Adamo, L. Zelante, et al. Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria Hum. Mol. Genet., February 1, 2001; 10(4): 305 - 316. [Abstract] [Full Text] [PDF]
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V. Dall'Asta, O. Bussolati, R. Sala, B. M. Rotoli, G. Sebastio, M. P. Sperandeo, G. Andria, and G. C. Gazzola Arginine transport through system y+L in cultured human fibroblasts: normal phenotype of cells from LPI subjects Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1829 - C1837. [Abstract] [Full Text] [PDF]
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 D. L. Jack, I. T. Paulsen, and M. H. Saier The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations Microbiology, August 1, 2000; 146(8): 1797 - 1814. [Abstract] [Full Text]
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 C. A Wagner, A. Broer, A. Albers, N. Gamper, F. Lang, and S. Broer The heterodimeric amino acid transporter 4F2hc/LAT1 is associated in Xenopus oocytes with a non-selective cation channel that is regulated by the serine/threonine kinase sgk-1 J. Physiol., July 1, 2000; 526(1): 35 - 46. [Abstract] [Full Text] [PDF]
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P. T.-Y. Ayuk, C. P. Sibley, P. Donnai, S. D'Souza, and J. D. Glazier Development and polarization of cationic amino acid transporters and regulators in the human placenta Am J Physiol Cell Physiol, June 1, 2000; 278(6): C1162 - C1171. [Abstract] [Full Text] [PDF]
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J. Kahn, F. Mehraban, G. Ingle, X. Xin, J. E. Bryant, G. Vehar, J. Schoenfeld, C. J. Grimaldi, F. Peale, A. Draksharapu, et al. Gene Expression Profiling in an in Vitro Model of Angiogenesis Am. J. Pathol., June 1, 2000; 156(6): 1887 - 1900. [Abstract] [Full Text] [PDF]
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D. P. Rajan, W. Huang, R. Kekuda, R. L. George, J. Wang, S. J. Conway, L. D. Devoe, F. H. Leibach, P. D. Prasad, and V. Ganapathy Differential Influence of the 4F2 Heavy Chain and the Protein Related to b0,+ Amino Acid Transport on Substrate Affinity of the Heteromeric b0,+ Amino Acid Transporter J. Biol. Chem., May 5, 2000; 275(19): 14331 - 14335. [Abstract] [Full Text] [PDF]
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Y. Fukasawa, H. Segawa, J. Y. Kim, A. Chairoungdua, D. K. Kim, H. Matsuo, S. H. Cha, H. Endou, and Y. Kanai Identification and Characterization of a Na+-independent Neutral Amino Acid Transporter That Associates with the 4F2 Heavy Chain and Exhibits Substrate Selectivity for Small Neutral D- and L-Amino Acids J. Biol. Chem., March 24, 2000; 275(13): 9690 - 9698. [Abstract] [Full Text] [PDF]
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W. A. Campbell, D. E. Sah, M. M. Medina, J. E. Albina, W. B. Coleman, and N. L. Thompson TA1/LAT-1/CD98 Light Chain and System L Activity, but Not 4F2/CD98 Heavy Chain, Respond to Arginine Availability in Rat Hepatic Cells. LOSS OF RESPONSE IN TUMOR CELLS J. Biol. Chem., February 25, 2000; 275(8): 5347 - 5354. [Abstract] [Full Text] [PDF]
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R. Zent, C. A. Fenczik, D. A. Calderwood, S. Liu, M. Dellos, and M. H. Ginsberg Class- and Splice Variant-specific Association of CD98 with Integrin beta Cytoplasmic Domains J. Biol. Chem., February 18, 2000; 275(7): 5059 - 5064. [Abstract] [Full Text] [PDF]
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Y. Kudo and C A R Boyd Heterodimeric amino acid transporters: expression of heavy but not light chains of CD98 correlates with induction of amino acid transport systems in human placental trophoblast J. Physiol., February 15, 2000; 523(1): 13 - 18. [Abstract] [Full Text] [PDF]
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J. Mykkanen, D. Torrents, M. Pineda, M. Camps, M. E. Yoldi, N. Horelli-Kuitunen, K. Huoponen, M. Heinonen, J. Oksanen, O. Simell, et al. Functional analysis of novel mutations in y+LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI) Hum. Mol. Genet., February 12, 2000; 9(3): 431 - 438. [Abstract] [Full Text] [PDF]
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 C Chiu, L. Ross, B. Cohen, H. Lester, and S. Gill The transporter-like protein inebriated mediates hyperosmotic stimuli through intracellular signaling J. Exp. Biol., January 12, 2000; 203(23): 3531 - 3546. [Abstract] [PDF]
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G. Rossier, C. Meier, C. Bauch, V. Summa, B. Sordat, F. Verrey, and L. C. Kuhn LAT2, a New Basolateral 4F2hc/CD98-associated Amino Acid Transporter of Kidney and Intestine J. Biol. Chem., December 3, 1999; 274(49): 34948 - 34954. [Abstract] [Full Text] [PDF]
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 R. Pfeiffer, J. Loffing, G. Rossier, C. Bauch, C. Meier, T. Eggermann, D. Loffing-Cueni, L. C. Kühn, and F. Verrey Luminal Heterodimeric Amino Acid Transporter Defective in Cystinuria Mol. Biol. Cell, December 1, 1999; 10(12): 4135 - 4147. [Abstract] [Full Text]
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A. Chairoungdua, H. Segawa, J. Y. Kim, K.-i. Miyamoto, H. Haga, Y. Fukui, K.'i. Mizoguchi, H. Ito, E. Takeda, H. Endou, et al. Identification of an Amino Acid Transporter Associated with the Cystinuria-related Type II Membrane Glycoprotein J. Biol. Chem., October 8, 1999; 274(41): 28845 - 28848. [Abstract] [Full Text] [PDF]
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D. P. Rajan, R. Kekuda, W. Huang, H. Wang, L. D. Devoe, F. H. Leibach, P. D. Prasad, and V. Ganapathy Cloning and Expression of a b0,+-like Amino Acid Transporter Functioning as a Heterodimer with 4F2hc Instead of rBAT. A NEW CANDIDATE GENE FOR CYSTINURIA J. Biol. Chem., October 8, 1999; 274(41): 29005 - 29010. [Abstract] [Full Text] [PDF]
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J. L. Sloan and S. Mager Cloning and Functional Expression of a Human Na+ and Cl--dependent Neutral and Cationic Amino Acid Transporter B0+ J. Biol. Chem., August 20, 1999; 274(34): 23740 - 23745. [Abstract] [Full Text] [PDF]
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M. Pineda, E. Fernandez, D. Torrents, R. Estevez, C. Lopez, M. Camps, J. Lloberas, A. Zorzano, and M. Palacin Identification of a Membrane Protein, LAT-2, That Co-expresses with 4F2 Heavy Chain, an L-type Amino Acid Transport Activity with Broad Specificity for Small and Large Zwitterionic Amino Acids J. Biol. Chem., July 9, 1999; 274(28): 19738 - 19744. [Abstract] [Full Text] [PDF]
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H. Segawa, Y. Fukasawa, K.-i. Miyamoto, E. Takeda, H. Endou, and Y. Kanai Identification and Functional Characterization of a Na+-independent Neutral Amino Acid Transporter with Broad Substrate Selectivity J. Biol. Chem., July 9, 1999; 274(28): 19745 - 19751. [Abstract] [Full Text] [PDF]
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H. Sato, M. Tamba, T. Ishii, and S. Bannai Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins J. Biol. Chem., April 23, 1999; 274(17): 11455 - 11458. [Abstract] [Full Text] [PDF]
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Y. Kanai, Y. Fukasawa, S. H. Cha, H. Segawa, A. Chairoungdua, D. K. Kim, H. Matsuo, J. Y. Kim, K.-i. Miyamoto, E. Takeda, et al. Transport Properties of a System y+L Neutral and Basic Amino Acid Transporter. INSIGHTS INTO THE MECHANISMS OF SUBSTRATE RECOGNITION J. Biol. Chem., June 30, 2000; 275(27): 20787 - 20793. [Abstract] [Full Text] [PDF]
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H. Sato, K. Kuriyama-Matsumura, T. Hashimoto, H. Sasaki, H. Wang, T. Ishii, G. E. Mann, and S. Bannai Effect of Oxygen on Induction of the Cystine Transporter by Bacterial Lipopolysaccharide in Mouse Peritoneal Macrophages J. Biol. Chem., March 23, 2001; 276(13): 10407 - 10412. [Abstract] [Full Text] [PDF]
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W. A. Campbell and N. L. Thompson Overexpression of LAT1/CD98 Light Chain Is Sufficient to Increase System L-Amino Acid Transport Activity in Mouse Hepatocytes but Not Fibroblasts J. Biol. Chem., May 11, 2001; 276(20): 16877 - 16884. [Abstract] [Full Text] [PDF]
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C. A. Fenczik, R. Zent, M. Dellos, D. A. Calderwood, J. Satriano, C. Kelly, and M. H. Ginsberg Distinct Domains of CD98hc Regulate Integrins and Amino Acid Transport J. Biol. Chem., March 16, 2001; 276(12): 8746 - 8752. [Abstract] [Full Text] [PDF]
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A. Chairoungdua, Y. Kanai, H. Matsuo, J. Inatomi, D. K. Kim, and H. Endou Identification and Characterization of a Novel Member of the Heterodimeric Amino Acid Transporter Family Presumed to be Associated with an Unknown Heavy Chain J. Biol. Chem., December 21, 2001; 276(52): 49390 - 49399. [Abstract] [Full Text] [PDF]
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