Disease relevance of SLC7A5

• These findings suggest that LAT1 could be one of the molecular targets in glioma therapy [1].
• Kaplan-Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p<0.0001) and for those with glioblastoma multiforme in particular (p=0.0001) [1].
• Overexpression of LAT1 in T24 cells using recombinant adenoviruses led to increased uptake of L-CSNO, whereas knockdown using a specific small interfering RNA led to decreased uptake [2].
• The specific inhibition of LAT1 in oral cancer cells could be a new rationale for anti-cancer therapy [3].
• LAT1 is proposed to be involved in the progression of malignant tumor. xCT (x- C-type transporter) functions to protect cells against oxidative stress, while its over-function may be damaging neurons leading to the exacerbation of brain damage after, brain ischemia [4].

Psychiatry related information on SLC7A5

• This proliferative phase, which begins on embryonic day 17 (E17), is induced by the interaction of a few specific neurons in the sex ganglia with a peripheral target, the male genitalia, during a critical period that extends from E13 to E16 [5].
• As phenylalanine excess in the brain leads to mental retardation in untreated patients with phenylketonuria, mutations of the LAT1 gene can be responsible for milder clinical manifestations (lower brain toxicity of hyperphenylalaninaemia) observed in some patients [6].

High impact information on SLC7A5

• Pbx1-/- embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day (E) 15 or E16 [7].
• The molecular nature of these transporters remains unknown, although expression of the human cell-surface glycoprotein 4F2 heavy chain (h4F2hc; CD98 in the mouse) is known to induce low levels of L- and/or y(+)L-type transport [8].
• Complementation of dominant suppression implicates CD98 in integrin activation [9].
• Here we identify a conserved exonic splicing silencer element (CE(16)) in E16 that interacts with hnRNP A/B proteins and plays a role in repression of E16 splicing during early erythropoiesis [10].
• The LAT1 and NAT1 factors were released from chromatin by extraction with a low-salt buffer and were soluble in 2% trichloroacetic acid, implying a relationship to high-mobility group (HMG) proteins [11].

Chemical compound and disease context of SLC7A5

• On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2-aminobicyclo-2 (2,2,1)-heptane-2-carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model [1].
• Kaposi's sarcoma-associated herpesvirus (KSHV) (human herpesvirus 8) binds to adherent target cell surface heparan sulfate molecules via its envelope glycoproteins gB and gpK8.1A, to integrins via gB, to the transporter CD98/xCT complex, and possibly to another molecule(s) [12].
• The deleterious effects on the brain of phenylketonuria are caused by the saturation of the blood-brain barrier large neutral amino acid transporter type 1 (LAT1) by high plasma phenylalanine concentrations [13].
• Human immunodeficiency virus type-1 envelope glycoprotein gp120 induces expression of fusion regulatory protein (FRP)-1/CD98 on CD4+ T cells: a possible regulatory mechanism of HIV-induced syncytium formation [14].

Biological context of SLC7A5

• Fluorescence in situ hybridization analysis using the cDNA assigned the CD98LC gene to the long arm of human chromosome 16 (16q24) [15].
• The predicted amino acid sequence suggested that CD98LC is a protein with multiple transmembrane domains and is almost identical to the amino acid transporter E16 [15].
• On the basis of the N-terminal sequence (63 amino acids) of purified CD98LC polypeptide, we have cloned a PCR fragment (155 bp) from a HeLa S3 cDNA library and finally obtained a full cDNA clone encoding the CD98LC [15].
• In malignant tumors, the LAT1 is highly expressed to support tumor cell growth [16].
• Carrier-mediated ornithine transport via the L-type amino acid transporter (LAT)1, LAT2, cationic amino acid transporter (CAT)-1, and y(+)LAT2 systems was evaluated by short interfering (si)RNA-mediated gene silencing [17].

Anatomical context of SLC7A5

• Resting monocytes and lymphocytes expressed CD98LC as analyzed by a newly isolated anti-CD98LC mAb, which showed cross-reactivity with insect Sf9 cells as well as with various mammalian cell lines [15].
• LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells [1].
• The affinity and the inhibition profiles of [14C]L-leucine uptake by various amino acids in the FOB and Saos2 cells were comparable with those for the LAT2 and LAT1 expressed in Xenopus oocytes, respectively [16].
• LAT1 is also essential for the permeation of amino acids and amino acid-related drugs through the blood-brain barrier [18].
• Northern blot, real-time quantitative PCR and immunofluorescence analyses have reveled that T24 cells express LAT1 in the plasma membrane together with its associating protein 4F2hc, whereas T24 cells do not express the other system L isoform LAT2 [18].

Associations of SLC7A5 with chemical compounds

• In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan [19].
• When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain [19].
• When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine [19].
• We have demonstrated also that LAT1 response to arginine availability is lost in transformed and tumorigenic cells such that expression is constitutively high [20].
• Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols [2].

Physical interactions of SLC7A5

• The 4F2hc/LAT1 complex has been suggested to be the most important molecular component responsible for this transport [21].

Other interactions of SLC7A5

• 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 [22].
• The expression of LAT1 mRNA was 100- and 15-fold greater than that of LAT2 in TR-iBRB2 and magnetically isolated rat retinal vascular endothelial cells, respectively [23].
• These include biosynthesis, cell-specific uptake or export (involving L-type amino acid transporter, organic anion transporter, organic cation transporter, or multidrug resistance transporter), as well as nuclear targeting and actions (the latter including TH receptor binding and histone acetylation/deacetylation) [24].

Analytical, diagnostic and therapeutic context of SLC7A5

• In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells [19].
• In addition, by Northern-blot analysis, these increments were found to be due to elevated levels of LAT1 and 4F2hc mRNA [25].
• Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function [26].
• Consistent with this, anti-TA1/E16 antibodies specifically immunoblotted the approximately 35-40-kDa light chain present upon immunoprecipitation of the human CD98 complex [27].
• LAT1 was identified by RT-PCR in rabbit corneal, SIRC, and human corneal RNA [28].

References