SLC7A6

SLC7A6 (y+LAT-2/LAT-2) is the light-chain subunit of a heteromeric amino acid transporter that must obligatorily heterodimerize with the heavy chain 4F2hc (CD98/SLC3A2) to traffic to the plasma membrane and reconstitute sodium-independent, exchanger-mode transport of small and large zwitterionic amino acids (system L/y+L activity); expressed alone it remains intracellular and transport-inactive (PMID:10391915). In polarized epithelia it operates at the basolateral membrane: in renal proximal tubule cells it drives net efflux of cysteine, with loss of function reducing transepithelial cystine flux and raising intracellular cysteine (PMID:12660317), and in renal opossum kidney cells it mediates broad Na+-independent uptake of neutral amino acids including L-DOPA, stimulated by acid pH and inhibited by BCH (PMID:11944084). Within the CD98/LAT-2 complex at the intestinal basolateral membrane, SLC7A6 transport kinetics are acutely tuned by a supramolecular assembly with ICAM-1, where CD98 versus ICAM-1 ligation reciprocally shift Km and Vmax and induce threonine phosphorylation of the complex (PMID:12716892). SLC7A6 transporter function feeds amino-acid-dependent mTORC1/S6K signaling, and its expression is restrained by a STAT5A→CDYL2 axis that lowers H3K4me3 at the SLC7A6 promoter (PMID:35314791). Tissue-specific roles include betaine uptake by cumulus cells for delivery to the oocyte via gap junctions (PMID:24599290).

1. 1999 High

   Established that SLC7A6 is not an autonomous transporter but a light chain requiring 4F2hc to reach the surface and confer system L exchange activity, defining its molecular architecture.

   Evidence Xenopus oocyte co-expression of tagged LAT-2 ± 4F2hc with uptake, trans-stimulation, and localization assays

   PMID:10391915

   Open questions at the time

   • No structural model of the heterodimer
   • Stoichiometry and substrate translocation mechanism not resolved
2. 2002 Medium

   Characterized the substrate range and regulatory properties of SLC7A6 transport, showing broad neutral amino acid (including L-DOPA) handling with pH and BCH sensitivity.

   Evidence Functional transport assays in OKLC/OKHC renal clonal lines with pharmacological inhibition and efflux/pH dependence

   PMID:11944084

   Open questions at the time

   • No genetic loss-of-function
   • Apical vs basolateral distribution differed from later epithelial findings
3. 2003 High

   Defined the physiological epithelial role of SLC7A6 as the basolateral system L exchanger driving net cysteine efflux in renal proximal tubule.

   Evidence Antisense knockdown in OK cells with transepithelial cystine flux and intracellular metabolite measurement

   PMID:12660317

   Open questions at the time

   • Effect shown in one cell line, not in vivo kidney
   • Contribution relative to other system L carriers not quantified
4. 2003 Medium

   Revealed that SLC7A6 transport kinetics are acutely regulated through a supramolecular CD98/LAT-2–ICAM-1 complex rather than being constitutive.

   Evidence Reciprocal co-IP, antibody cross-linking, kinetic and phosphorylation assays in polarized Caco2-BBE monolayers

   PMID:12716892

   Open questions at the time

   • Signaling kinase mediating threonine phosphorylation not identified
   • Physiological trigger for ICAM-1 ligation in vivo unknown
5. 2005 Medium

   Showed SLC7A6 functionally interacts with SLC7A7 (y+LAT-1) in a multiheteromeric arrangement, explaining incomplete compensation in lysinuric protein intolerance.

   Evidence Dominant-negative SLC7A7 mutant expression in oocytes and mammalian cells with transport epistasis analysis

   PMID:15756301

   Open questions at the time

   • Direct physical evidence for a shared complex limited
   • Composition of the multiheteromer not defined
6. 2014 Medium

   Identified a tissue-specific transport role for SLC7A6 in cumulus cell betaine uptake delivered to the oocyte, extending its substrate physiology beyond renal epithelia.

   Evidence Expression profiling, pharmacological transport characterization, and gap-junction inhibition in mouse cumulus-oocyte complexes

   PMID:24599290

   Open questions at the time

   • No genetic knockdown of SLC7A6 in this context
   • Identity established by inference from y+L profile
7. 2022 Medium

   Placed SLC7A6 downstream of an epigenetic regulatory axis and upstream of amino-acid-driven growth signaling, linking its expression to mTORC1/S6K output.

   Evidence CDYL2 gain/loss-of-function, ChIP for H3K4me3 at the SLC7A6 promoter, and mTORC1/S6K readouts in hepatocellular carcinoma models

   PMID:35314791

   Open questions at the time

   • Direct demonstration that transporter activity (not protein level) drives mTORC1 not isolated
   • Single tumor type
8. 2024 Medium

   Distinguished an intron-retention isoform of SLC7A6 with a tumor-suppressive effect on colon cancer growth via PI3K-Akt-mTOR signaling.

   Evidence siRNA knockdown of SLC7A6-RI, xenografts, p-mTOR/PCNA western blots, and TCGA COAD analysis

   PMID:39403788

   Open questions at the time

   • Mechanism linking the RI isoform to mTOR not resolved
   • Relationship between RI isoform and canonical transporter function unclear
9. 2025 Low

   Proposed a redox-related substrate (oxidized glutathione) for SLC7A6 linking it to ferroptosis regulation.

   Evidence AlphaFold3 prediction of SLC7A6–GSSG interaction with biochemical GSSG/GSH/NO assays after knockdown

   PMID:41043754

   Open questions at the time

   • Structural prediction only, no experimental structure
   • No direct transport reconstitution of GSSG

• How SLC7A6 transport activity is mechanistically coupled to mTORC1 signaling and whether GSSG is a genuine transported substrate remain unresolved.
• No experimental structure of the SLC7A6/4F2hc heterodimer
• Direct substrate-flux link to mTORC1 not established
• GSSG transport not demonstrated in a reconstituted system