Human Transporters

ASCT2New

ASCT2 (Alanine/Serine/Cysteine-preferring Transporter 2)

Aliases: AAAT, ATBO

Gene name: Solute carrier family 1 member 5 (SLC1A5)

 

Summary

ASCT2 is a ubiquitously expressed, broad-specificity, sodium-dependent neutral amino acid exchanger. Along with LAT1, a sodium-independent amino acid antiporter, ASCT2 is thought to be involved in the “harmonization” of extracellular and intracellular amino acid pools. ASCT2 displays functional asymmetry, i.e. it transports some substrates only inwardly while others bidirectionally. Cysteine, initially believed to be a substrate, later turned out to be a non-transported modulator. The prime function of ASCT2 is the cellular import of the conditionally essential amino acid glutamine. In a ternary antiport mechanism, extracellular glutamine accompanied by Na+ is exchanged with another neutral amino acid from the intracellular pool. Glutamine is a versatile metabolite that can be utilized both as an energy source and a biosynthetic building block, and rapidly proliferating cells often vastly overconsume this amino acid. Physiological processes like T-cell activation, as well as the growth of many cancer types heavily depend on ASCT2-mediated glutamine uptake. ASCT2 and LAT1 are coordinately overexpressed in multiple forms of cancer, and at least in some of them a functional cooperation between the two is required to maintain mTORC1 signaling. Inhibition of ASCT2 has effectively attenuated tumor growth in preclinical models, and the modulation of ASCT2 is regarded as a promising anticancer strategy. Although selective and potent inhibitors of ASCT2 have been identified and are being sought after, no currently approved drug is known to interfere with ASCT2 function, and the FDA or EMA guidelines contain no recommendations on testing interactions of NCEs with ASCT2.

 

Localization

Under physiological conditions, ASCT2 is distributed ubiquitously in the body, with protein expression detected in the lung, skeletal muscle, large intestine, kidney, testis, T cells, brain, and adipose tissue (Scalise, Front Cell Dev Biol 2018). In polarized epithelia such as intestinal or renal proximal tubule epithelial cells, ASCT2 is localized to the apical membrane domain (Pochini, Front Chem 2014). Aberrant overexpression of ASCT2, often in parallel with upregulation of LAT1, was documented in a wide variety of malignant tumors (see Clinical significance). Very recently, a shorter transcript variant of ASCT2 has been shown to localize to the mitochondria in cancer cells (Yoo, Cell Metab 2019).

 

Function, physiology, and clinically significant polymorphisms

Both mouse and human ASCT2 were cloned and characterized in 1996 (Utsunomiya-Tate, J Biol Chem 1996; Kekuda, J Biol Chem 1996). Amino acid identity of human ASCT2 with the rat and mouse orthologs is 79 and 82%, respectively. The human SCL1A5 gene is located at 19q13.3 and contains 8 exons. The longest of three alternative transcripts encodes a 541-amino acid polypeptide with 8 transmembrane helices. Beside this extensively investigated major isoform, a shorter transcript variant lacking exon 1, encoding a 339-amino acid protein with a mitochondrial targeting signal, has recently been shown to be expressed in multiple cancer types under the control of HIF-2α (Yoo, Cell Metab 2019). As comparatively little is known about the mitochondrial variant, the rest of this text refers to the plasma membrane isoform of ASCT2.

Cryo-EM imaging has confirmed that monomers of ASCT2, each organized into a fixed (scaffold) and an elevator (transport) domain, assemble into homotrimers in the membrane (Garaeva 2018). N-glycosylation of ASCT2 is critical for trafficking to the membrane but not for intrinsic transport function (Console, BBA 2015).

Functional studies conducted with the purified rat protein have elucidated a peculiar three-substrate antiport mechanism, whereby the exchange of an extracellular neutral amino acid with an intracellular one is accompanied by the concomitant uptake of a Na+ ion with a 1:1:1 stoichiometry (Oppedisano, BBA 2007). ASCT2 exhibits both functional and kinetic asymmetry (Scalise, BBA 2016). Functional asymmetry refers to its ability to transport glutamine, serine, asparagine, and threonine in both directions, but alanine, valine, and methionine in the inward direction only. Kinetic asymmetry denotes a differential affinity to its substrates on the extracellular (Km in the micromolar range) versus the intracellular (Km in the millimolar range) side, which is in good agreement with the physiological concentrations of each substrate. Contrary to initial assumptions, cysteine is a modulator and not a substrate of ASCT2. Extracellular cysteine is not only a potent competitive inhibitor of glutamine uptake, but at higher concentrations it triggers unidirectional glutamine efflux without itself being inwardly transported. This modulatory function of cysteine, exerted through a putative allosteric site, is speculated to endow ASCT2 with a redox sensing capacity (Scalise, FEBS Lett 2015).

The major function of ASCT2 is the import of extracellular glutamine by exchange with another neutral amino acid such as serine, asparagine, or threonine from the intracellular pool. Glutamine is a conditionally essential amino acid: albeit cells can synthesize it de novo, few cell types are self-sufficient on glutamine and most tissues, especially those under increased metabolic demand, depend on external supply. Once in the cell, glutamine can be utilized in a variety of ways (Bhutia and Ganapathy, BBA 2016): it can enter the Krebs cycle to produce energy, or converted via reductive carboxylation into citrate to support lipid synthesis; its carbon chain and nitrogens can be incorporated into nucleobases or other amino acids; and it contributes in multiple ways to the biosynthesis of glutathione, a redox buffer that protects cells against oxidative stress. On the organismal level, glutamine also acts as a nitrogen carrier that shuttles ammonium from peripheral tissues, especially skeletal muscle, to the kidney. In accordance with such a multiplicity of roles, glutamine is the most abundant amino acid in human plasma with a steady-state concentration of 0.5-0.8 mM.

Since glutamine uptake is too important to be trusted on a single protein, this task is shared among multiple classes of broad-specificity amino acid transporters, and the likely reason why Slc1a5-null mice display no obvious phenotype (Ni, Nat Metab 2019) is compensation by functionally overlapping glutamine uptake systems, primarily the SLC38 family of sodium-coupled neutral amino acid transporters (SNATs). Thus, ASCT2 is probably dispensable in most mammalian tissues under healthy conditions. The few physiological processes in which ASCT2-mediated transport has been obligatorily implicated include T-cell activation (Nakaya, Immunity 2014) and the glutamine-glutamate cycle in the brain (Bröer, J Neurochem 1999) and the placenta (Torres-Zamorano, BBRC 1998). Still in the brain, ASCT1 and 2 were shown to transport D-serine, a co-agonist of NMDA-type glutamate receptors (Foster, PLoS One 2016).

Independently from its transporter function, ASCT2 is a receptor for retroviruses in nonhuman mammals, and mediates syncytium formation induced by fusogenic retroviral envelope proteins (Tailor, J Virol 1999). In humans, ASCT2 has retained this function as a receptor of syncytin-1, an endogenized retroviral envelope protein that promotes placental syncytiotrophoblast formation (Kudo and Boyd, Placenta 2002) and osteoclast fusion (Søe, Bone 2011).

Over 4000 SNPs of SLC1A5 are reported in the NCBI dbSNP database; however, apart from two variants suggested to associate with cancer (Savas 2006, Sillé 2012) and two other variants positively linked to human longevity (D’Aquila 2017), the significance of most SLC1A5 SNPs is unclear.

 

Clinical significance

ASCT2 has been most extensively studied for its role in cancer. Metabolic reprogramming of cancer often involves increased utilization of glutamine both as an energy source and a biosynthetic building block, which is also referred to as “glutamine addiction”. Overexpression of ASCT2, usually in parallel with LAT1, is driven by oncogenes like MYC (Dang 2009) and was observed in cancers of the prostate, lung, breast, kidney, the gastrointestinal tract and liver, the female reproductive tract, and the nervous system (Scalise, Front Oncol 2017). ASCT2 was also shown to be critical for leukemia formation in a mouse model, and was suggested as a potential therapeutic target (Ni, Nat Metab 2019).

According to a model originally proposed by Fuchs and Bode (Fuchs & Bode 2005) and experimentally confirmed by Nicklin et al. (Nicklin, Cell 2009), ASCT2 and LAT1 are functionally coupled in cancer cells: their cooperation maintains mTOR signaling, thereby supporting proliferation while preventing autophagy and apoptosis. In this model, glutamine imported by ASCT2 is exchanged for essential amino acids (EAAs) such as leucine by LAT1, and EAAs ensure sustained mTORC1 kinase activity. Pharmacological blockade of ASCT2 by γ-L-glutamyl-p-nitroanilide (GPNA) suppressed glutamine uptake, mTORC1 signaling, and cell growth in human triple-negative basal-like breast cancer cell lines (van Geldermalsen, Oncogene 2016).

Such successes in vitro have motivated the development of more potent and specific inhibitors of ASCT2. Aided by a homology model built on the atomic structure of the archaean aspartate transporter GltPh, a family of 2-amino-4-bis(aryloxybenzyl)aminobutanoic acid (AABA) inhibitors was discovered (Schulte, Bioorg Med Chem Lett 2016), the most potent of which, later named V-9302, exhibited >100-fold improved potency over GPNA (IC50 of V-9302 vs. GPNA, 9.6 μM vs. ~1 mM). Further preclinical development of V-9302 seemed to justify high expectations as treatment with the drug decreased viability of lung, breast, and colorectal cancer cell lines, and arrested the growth of human cell line xenografts in nude mice (Schulte, Nat Med 2018).

The ASCT2-centered interpretation of these results, however, became strongly challenged by subsequent studies that demonstrated an inhibitory effect of AABA compounds independent of ASCT2, and identified SNAT2 and LAT1 as the true molecular targets of V-9302 (Bröer, Front Pharmacol 2018). These data favor an alternative model of glutamine flow in cancer cells in which SNAT1 (the “loader”) is primarily responsible for glutamine import, ASCT2 and LAT1 (the “harmonizers”) jointly equilibrate intracellular and extracellular neutral amino acid pools, and SNAT2 (the “rescue” transporter) is induced upon disruption of amino acid balance (Bröer, J Biol Chem 2016). Further corroboration that ASCT2 and LAT1 are harmonizers rather than drivers of amino acid accumulation came from experiments where abrogation of either ASCT2 or LAT1 in human liver cancer cell lines failed to suppress mTOR signaling or proliferation, and amino acid levels, albeit initially reduced, recovered over time in the knockdown cells (Bothwell, Int J Mol Sci 2018). Knockout of ASCT2 from colon and lung adenocarcinoma cell lines significantly reduced glutamine import without affecting leucine uptake or mTORC1 activity, which speaks against functional coupling between ASCT2 and LAT1 in this system (Cormerais 2018).

Nevertheless, ASCT2-KO tumors exhibited reduced growth as xenografts in vivo (Cormerais 2018); also, in a very recent study using human head and neck squamous cell carcinoma cell cultures and xenografts, silencing of ASCT2 alone was able to increase oxidative stress, suppress the mTORC1 pathway, and attenuate tumor growth, albeit the effect was enhanced by simultaneous blockade of SNAT2 with V-9302 (Zhang, Br J Cancer 2020). While the relative contribution of various transporters to glutamine supply may be context-dependent, ASCT2 is still regarded as an attractive anticancer target, and the development of novel inhibitors – now using homology models based on the crystal structure of a closer relative, the human glutamate transporter EAAT1 (SCL1A3) – continues (Garibsingh, Front Chem 2018; Ndaru, J Gen Physiol 2019). The latest family of inhibitors built around sulfonamide and sulfonic acid ester scaffolds explore previously unvisited regions of the chemical design space (Ndaru 2019).

 

Regulatory requirements

No currently approved drug is known to interfere with ASCT2 function, and the FDA or EMA guidelines contain no recommendations on testing interactions of NCEs with ASCT2.

 

Table: Summary information for ASCT2

Location

Endogenous substrates

In vitro substrates used experimentally

Substrate drugs

Inhibitors

ubiquitous; known physiological roles in T cells, brain, placenta; overexpressed in cancer

neutral amino acids; preferred uptake substrate: glutamine

glutamine (mostly), alanine

none known

GPNA, benzylserine, benzylcysteine, O-(4-phenylbenzoyl)-L-serine, (R)-γ-(4-biphenylmethyl)-L-proline, AABA compounds (?), sulfonamide/sulfonic acid ester inhibitors

References

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Garaeva AA, Oostergetel GT, Gati C, Guskov A, Paulino C, Slotboom DJ. Cryo-EM structure of the human neutral amino acid transporter ASCT2. Nat Struct Mol Biol. 2018 Jun;25(6):515-521. doi: 10.1038/s41594-018-0076-y. Epub 2018 Jun 5. PubMed PMID: 29872227.

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Kudo Y, Boyd CA. Changes in expression and function of syncytin and its receptor, amino acid transport system B(0) (ASCT2), in human placental choriocarcinoma BeWo cells during syncytialization. Placenta. 2002 Aug;23(7):536-41. PubMed PMID: 12175968.

Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D. The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. J Virol. 2002 Jul;76(13):6442-52. PubMed PMID: 12050356; PubMed Central PMCID: PMC136247.

Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014 May 15;40(5):692-705. doi: 10.1016/j.immuni.2014.04.007. Epub 2014 May 1. PubMed PMID: 24792914; PubMed Central PMCID: PMC4074507.

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Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009 Feb 6;136(3):521-34. doi: 10.1016/j.cell.2008.11.044. PubMed PMID: 19203585; PubMed Central PMCID: PMC3733119.

Oppedisano F, Pochini L, Galluccio M, Indiveri C. The glutamine/amino acid transporter (ASCT2) reconstituted in liposomes: transport mechanism, regulation by ATP and characterization of the glutamine/glutamate antiport. Biochim Biophys Acta. 2007 Feb;1768(2):291-8. Epub 2006 Sep 16. PubMed PMID: 17046712.

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Utsunomiya-Tate N, Endou H, Kanai Y. Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem. 1996 Jun 21;271(25):14883-90. PubMed PMID: 8662767.

van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O'Toole SA, Rasko JE, Holst J. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2016 Jun 16;35(24):3201-8. doi: 10.1038/onc.2015.381. Epub 2015 Oct 12. PubMed PMID: 26455325; PubMed Central PMCID: PMC4914826.

Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, Kim JK, Heo Y, Lee HS, Lee MY, Lee CW, Kang JS, Kim YH, Lee J, Choi J, Hwang GS, Bang S, Han JM. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metab. 2019 Dec 13. pii: S1550-4131(19)30664-3. doi: 10.1016/j.cmet.2019.11.020. [Epub ahead of print] PubMed [citation] PMID: 31866442

Zhang Z, Liu R, Shuai Y, Huang Y, Jin R, Wang X, Luo J. ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br J Cancer. 2020 Jan;122(1):82-93. doi: 10.1038/s41416-019-0637-9. Epub 2019 Dec 10. PubMed PMID: 31819178.

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