LAT2

Official Full Name

linker for activation of T cells family member 2

Organism

Homo sapiens

GeneID

7462

Background

This gene is one of the contiguous genes at 7q11.23 commonly deleted in Williams syndrome, a multisystem developmental disorder. This gene consists of at least 14 exons, and its alternative splicing generates 3 transcript variants, all encoding the same protein. [provided by RefSeq, Jul 2008]

Synonyms

LAB; NTAL; WSCR5; WBSCR5; HSPC046; WBSCR15;

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Detailed Information

Recent Progress

Researchers had a major breakthrough with the overexpression of a recombinant 4F2hc-LAT2. Microgram amounts of purified protein made possible the reconstruction of the first 3D map of a human HAT (human amino acids transporter). They reported the important stabilization of purified human 4F2hc-LAT2. The stabilization of the purified human 4F2hc-LAT2 complex paves the way towards the elucidation of the working mechanism of this important protein complex at the molecular level.

LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. LAT2 plays a role in placental uptake. System L plays a crucial role in placental transport of essential amino acids such as leucine and methionine and thus has been assumed to also transport MeHg-l-cysteine (methylmercury) across the placenta. Upon the downregulation of large neutral amino acids transporter (LAT)2 and 4F2 cell-surface antigen heavy chain (4F2hc), respectively, the levels of leucine in BeWo cells are significantly reduced compared to controls. The uptake of methionine was reduced upon LAT2 down-regulation as well as methylmercury uptake after 4F2hc silencing. These findings suggested an important role of system L in the placental uptake of the metal. Comparing the cellular accumulation of mercury, leucine, and methionine, it can be assumed that both LAT2 and 4F2 play significant roles in placental uptake due to their roles in system L.

The LAT2 also participated in thyroid hormones transportation across cell membranes. Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. Coinjection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased level of 3,3’-diiodo-L-thyronine (3,3’-T2) and to some extent also enhanced T3 transport. Data indicated that Lat2 compared to other thyroid hormone transporters prefers 3,3’-T2 as the substrate. Thus, Lat2 might contribute to the availability of thyroid hormone by importing and/or exporting 3,3’-T2, which is generated either by T3 inactivation or by rapid deiodinase 1-mediated rT3 degradation. As Lat2 is expressed in neurons and in the choroid plexus, the results supported a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development.

LAT2 has a strong connection with tumor as well. LAT1 and LAT2 were overexpressed in both PHEO (pheochromocytoma) and MTC (medullary thyroid carcinoma) by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO than in MTC. Furthermore, researchers found a good correlation between LAT1/2 and GLUT1 expression levels. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. This study provided experimental evidence of the overexpression in some cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT2 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells.

References:

Balthasar, Christina, et al. "Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter." International Journal of Molecular Sciences 18.8(2017):1730.
Cicone, F, et al. "Expression of large neutral amino acid transporters LAT1 and LAT2 in medulloblastoma. " Brain Tumor Pathology 34.4(2017):1-3.
Kinne, A, et al. "Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3'-Diiodothyronine across the Plasma Membrane. " European Thyroid Journal 4.Suppl 1(2015):42.
Barollo, S, et al. "Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors." Plos One 11.5(2016):e0156044.
Kinne, Anita, et al. "Involvement of Lat2 in the transport of 3,3[prime]-T2 across the plasma membrane and first structural insights into transport mechanisms by homology model generation." Endocrine (2014).

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