Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family

Mastroberardino, Luca; Spindler, Benjamin; Pfeiffer, Rahel; Skelly, Patrick J.; Loffing, Johannes; Shoemaker, Charles B.; Verrey, François

doi:10.1038/26246

Cited by 504 publications

(503 citation statements)

References 21 publications

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“…Similar transport properties were reported for the rat homologue TA1 [8]. We showed that XAmAT-L-lc and h4F2hc form a heterodimer (AmAT-L) that migrates as a band of approximately 120 kDa on SDS-PAGE in non-reducing conditions and that, in the presence of a reducing agent, additional bands of 80 kDa and 40 kDa appear, indicating that heavy and light chains are linked by a disul¢de bond [7]. SPRM1, a Schistosoma mansoni membrane protein with 40% identity to XAmAT-L-lc was also shown to heterodimerize with h4F2hc.…”

Section: Introductionsupporting

confidence: 82%

“…2A shows the SDS-PAGE analysis of immunopreciptiations made with the anti-h4F2hc antibody. The expected band of 80 kDa appeared in oocytes expressing h4F2hc only (lanes 1, 2, 11, 12), and, in contrast, no protein was precipitated when oocytes were injected with either of the light chains alone (lanes 3, 7, 13, 17) [7]. In non-reducing conditions, coinjection of h4F2hc/XAmAT-L-lc or h4F2hc/SPRM1 resulted, as previously shown, in the appearance of a band at V120 kDa, which corresponds to a heterodimer (lanes 14, 18).…”

Section: Coimmunoprecipitation Of Heavy and Light Chains Dependsmentioning

confidence: 97%

“…localized intracellularly when expressed alone, and required coexpression of h4F2hc to localize at the surface [7]. To test whether h4F2hc is able to promote the surface expression of a non-covalently bound AmAT-light chain, double immuno£uorescence experiments were performed using antibodies to h4F2hc and SPRM1.…”

Section: Amino Acid Transport Is Only Reduced In the Absence Of Covalmentioning

confidence: 99%

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Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond

et al. 1998

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The protein mediating system L amino acid transport, AmAT-L, is a disulfide-linked heterodimer of a permease-related light chain (AmAT-L-lc) and the type II glycoprotein 4F2hc/ CD98. The Schistosoma mansoni protein SPRM1 also heterodimerizes with h4F2hc, inducing amino acid transport with different specificity. In this study, we show that the disulfide bond is formed by heavy chain C109 with a Cys residue located in the second putative extracellular loop of the multi-transmembrane domain light chain (C164 and C137 for XAmAT-L-lc and SPRM1, respectively). The non-covalent interaction of Cysmutant subunits is not sufficient to allow coimmunoprecipitation, but cell surface expression of the light chains is maintained to a large extent. The non-covalently linked transporters display the same transport characteristics as disulfide bound heterodimers, but the maximal transport rates are reduced by 30^80%.z 1998 Federation of European Biochemical Societies.

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Section: Introductionsupporting

confidence: 82%

Section: Coimmunoprecipitation Of Heavy and Light Chains Dependsmentioning

confidence: 97%

Section: Amino Acid Transport Is Only Reduced In the Absence Of Covalmentioning

confidence: 99%

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Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond

et al. 1998

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“…30 Importantly, CD98 is the main heterodimerization partner for 6 amino acid transporters, which are dependent on the CD98 heavy chain for their localization and proper function. 23 Among those 6 transporters, the bi-directional transporters LAT-1 and LAT-2 export nonessential glutamine to enable the uptake of essential amino acids, which in turn activate the mammalian target of the rapamycin pathway promoting cell growth and survival. 31 Although biologically active small molecules against CD98-associated light chains have been identified, anti-CD98 antibodies provide another approach to modifying amino acid transport.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

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CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

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“…L-type amino acid transporter 1 (LAT1) is a neutral amino acid transporter and is essential for the transport of large neutral amino acids [6,7]. It has been shown that LAT1 is overexpressed in some malignant tumor cells such as KB human oral epidermoid carcinoma cells [8], esophageal carcinoma [9], Barrett's adenocarcinoma [10], astrocytic tumors [11,12], lung adenocarcinoma [13], oral cancer [14] and osteogenic sarcoma cells [15].…”

Section: Introductionmentioning

confidence: 99%

Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression

Liang

Cho

Williams

et al. 2010

Nucl Med Mol Imaging

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Purpose L-type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. Methods LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with anti-1-amino-3-[ 18 F]fluorocyclobutane-1-carboxylic acid (anti-[ 18 F]FACBC) PET was assessed for its diagnostic biomarker potential. Results Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high-grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced-stage breast cancer. Furthermore, the blockade of LAT1 with its inhibitor, 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, anti-[ 18 F]FACBC, has been demonstrated to be an excellent PET tracer for the non-invasive imaging of malignant breast cancer using an orthotopic animal model. Conclusions The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. Anti-[ 18 F]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging.

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Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family

Cited by 504 publications

References 21 publications

Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond

Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond

Antitumor activity of an anti‐CD98 antibody

Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression

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