Amino Acid Transporter

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Yoshikatsu Kanai - One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationship of a novel series of inhibitors for cancer type Transporter l type Amino Acid Transporter 1 lat1
    Journal of Pharmacological Sciences, 2017
    Co-Authors: Pornparn Kongpracha, Shushi Nagamori, Pattama Wiriyasermkul, Yoko Tanaka, Kazuko Kaneda, Suguru Okuda, Ryuichi Ohgaki, Yoshikatsu Kanai
    Abstract:

    Abstract L-type Amino Acid Transporter 1 (LAT1) is known as a cancer-type Amino Acid Transporter. In cancer cells, LAT1 is responsible for the cellular uptake of many essential Amino Acids including leucine that activates mechanistic/mammalian target of rapamycin (mTOR), regulating cancer cell growth. In this study, we designed a novel series of LAT1 inhibitors, SKN101–105, based on the structure of triiodothyronine (T3), a known LAT1 blocker. The compounds consist of core structure of 2-Amino-3-[3,5-dichloro-4-(naphthalene-1-methoxy)-phenyl]-propanoic Acid and different modifications on the naphthalene. Among them, the compounds including SKN103 with a modified phenyl group at C-7 position of naphthalene inhibited LAT1-mediated leucine transport, whereas SKN102 with a phenyl group at C-6 position did not, indicating the importance of the position of substituents on the naphthalene for the interaction with LAT1. SKN103 was suggested to be a non-transportable blocker rather than a substrate of LAT1 and inhibited LAT1 in a competitive manner with the K i value of 2.1 μM. SKN103 suppressed mTOR activity and the growth of cancer cells. Moreover, SKN103 in combination with cisplatin additively enhanced the growth inhibition in cancer cells. This study provides an additional insight into the structure-activity relationship of LAT1 ligands, which could lead to designing desirable LAT1 inhibitors.

  • regulation of Amino Acid Transporter trafficking by mtorc1 in primary human trophoblast cells is mediated by the ubiquitin ligase nedd4 2
    Clinical Science, 2016
    Co-Authors: Fredrick J Rosario, Yoshikatsu Kanai, Theresa L. Powell, Kris Genelyn Dimasuay, Thomas Jansson
    Abstract:

    Changes in placental Amino Acid transfer directly contribute to altered fetal growth, which increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Placental Amino Acid transfer is critically dependent on the expression of specific Transporters in the plasma membrane of the trophoblast, the transporting epithelium of the human placenta. However, the molecular mechanisms regulating this process are largely unknown. Nedd4-2 is an ubiquitin ligase that catalyses the ubiquitination of proteins, resulting in proteasomal degradation. We hypothesized that inhibition of mechanistic target of rapamycin complex 1 (mTORC1) decreases Amino Acid uptake in primary human trophoblast (PHT) cells by activation of Nedd4-2, which increases Transporter ubiquitination resulting in decreased Transporter expression in the plasma membrane. mTORC 1 inhibition increased the expression of Nedd4-2, promoted ubiquitination and decreased the plasma membrane expression of SNAT2 (an isoform of the System A Amino Acid Transporter) and LAT1 (a System L Amino Acid Transporter isoform), resulting in decreased cellular Amino Acid uptake. Nedd4-2 silencing markedly increased the trafficking of SNAT2 and LAT1 to the plasma membrane, which stimulated cellular Amino Acid uptake. mTORC1 inhibition by silencing of raptor failed to decrease Amino Acid transport following Nedd4-2 silencing. In conclusion, we have identified a novel link between mTORC1 signalling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental Amino Acid Transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth.

  • asc Amino Acid Transporter 2 asct2 as a novel prognostic marker in non small cell lung cancer
    British Journal of Cancer, 2014
    Co-Authors: Kimihiro Shimizu, Noriaki Sunaga, Kyoichi Kaira, Hideyuki Tominaga, Noboru Oriuchi, Yoshikatsu Kanai, Shushi Nagamori, Yoshio Tomizawa, Osamu Kawashima, Masanobu Yamada
    Abstract:

    ASC Amino-Acid Transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer

  • Correlation of L-type Amino Acid Transporter 1 and CD98 expression with triple negative breast cancer prognosis.
    Cancer science, 2011
    Co-Authors: Mio Furuya, Yoshikatsu Kanai, Jun Horiguchi, Hiroki Nakajima, Tetsunari Oyama
    Abstract:

    Triple negative breast cancer (TNBC) is a heterogeneous, aggressive cancer for which there is no effective chemotherapy or targeted therapy. We aimed to evaluate L-type Amino Acid Transporter (LAT) 1 and CD98 expression immunohistochemically in patients with breast cancer, especially TNBC. Out of 129 patients, LAT1 was positive in 56 patients (43.4%), and CD98 was positive in 41 patients (31.8%). The positive ratio of LAT1 expression in luminal A cases was 7.9%, 30.0% in luminal B cases, 71.4% in HER2 cases and 64.0% in TN cases. HER2 and TN subtypes expressed LAT1 and CD98 at higher levels than luminal A and B subtypes (both P 

  • l type Amino Acid Transporter 1 inhibitors inhibit tumor cell growth
    Cancer Science, 2010
    Co-Authors: Koji Oda, Noriko Hosoda, Hiroshi Endo, Kunio Saito, Kenji Tsujihara, Michio Yamamura, Takeshi Sakata, Naohiko Anzai, Michael F Wempe, Yoshikatsu Kanai
    Abstract:

    Most tumor cell membranes overexpress L-type Amino Acid Transporter 1, while normal cell membranes contain l-type Amino Acid Transporter 2; both are Na(+)-independent Amino Acid Transporters. Therefore, compounds that selectively inhibit L-type Amino Acid Transporter 1 offer researchers with a novel cancer molecular target. Synthetic chemistry efforts and in vitro screening have produced a variety of novel compounds possessing high in vitrol-type Amino Acid Transporter 1 selectivity; KYT-0353 was one such compound. The present studies illustrate that KYT-0353 inhibited (14)C-leucine uptake and cell growth in human colon cancer-derived HT-29 cells; IC(50)s were 0.06 microm and 4.1 microm, respectively. KYT-0353 also inhibited (14)C-leucine uptake in mouse renal proximal tubule cells expressing l-type Amino Acid Transporter 1, and inhibited cell growth; IC(50)s were 0.14 microm and 16.4 microm, respectively. Compared to control animals, intravenously administered KYT-0353 (12.5 mg/kg and 25.0 mg/kg) showed statistically significant growth inhibition against HT-29 tumors transplanted to nude mice with maximal inhibition ratios of 65.9% and 77.2%, respectively. Body weight increase with time--a safety indicator--was slightly depressed at 12.5 mg/kg and 25.0 mg/kg with maximal ratios of 3.7% (day 2) and 6.3% (day 11), respectively. Thus, KYT-0353 showed significant growth inhibitory effects on HT-29 cells both in vitro and in vivo, whereas it only caused a slight body weight depression. Therefore, KYT-0353 appears to have potential as a novel anti-tumor agent, presumably via selective in vivol-type Amino Acid Transporter 1 inhibition.

Hitoshi Endou - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of the Amino Acid Transporter lat1 demonstrates anti neoplastic activity in medulloblastoma
    Journal of Cellular and Molecular Medicine, 2019
    Co-Authors: Yann Cormerais, Hitoshi Endou, Michael F Wempe, Marina Pagnuzziboncompagni, Sandra Schrotter, Sandy Giuliano, Eric Tambutte, Gilles Pages, Jacques Pouyssegur, Vincent Picco
    Abstract:

    Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type Amino Acid Transporter 1 (LAT1) is an essential Amino Acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.

  • inhibition of the Amino Acid Transporter lat1 demonstrates anti neoplastic activity in medulloblastoma
    bioRxiv, 2019
    Co-Authors: Yann Cormerais, Hitoshi Endou, Michael F Wempe, Marina Pagnuzziboncompagni, Sandra Schrotter, Sandy Giuliano, Eric Tambutte, Gilles Pages, Jacques Pouyssegur, Vincent Picco
    Abstract:

    ABSTRACT Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type Amino Acid Transporter 1 (LAT1) is an essential Amino Acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, the present study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.

  • L-type Amino Acid Transporter-1 expressed in human astrocytomas, U343MGa.
    Biological & pharmaceutical bulletin, 2007
    Co-Authors: Shinji Asano, Arthit Chairoungdua, Hitoshi Endou, Megumi Kameyama, Ayako Oura, Anna Morisato, Hideki Sakai, Yoshiaki Tabuchi, Yoshikatsu Kanai
    Abstract:

    LAT1 (L-type Amino Acid Transporter 1), one of the L-type Amino Acid Transporters, transports the branched and aromatic Amino Acids. LAT1 requires the heavy chain of 4F2 antigen (4F2hc) for the functional expression as an Amino Acid Transporter. The expression of this Transporter is up-regulated in tumor cells and rapidly-growing cells to support their proliferation. Here, we studied the expression of LAT1 and 4F2hc in human cultured cells by real-time PCR and Western blot, and found that human brain astrocytomas, U343MGa, highly expressed LAT1 and 4F2hc mRNAs and proteins. The uptake of [14C]leucine by U343MGa cells is Na+-independent and inhibited by BCH (2-Amino-2-norbornane carboxylic Acid), and branched and aromatic Amino Acids, indicating that the LAT1 is expressed at the cell surface. Pulse chase labeling and surface labeling experiments of this cell line indicate that the protein synthesis of LAT1 and 4F2hc is slow, however, the heterodimeric complex assembled in the cells is very stable, and that the disulfide bond between the LAT1 and 4F2hc is not directly involved in the stability of the heterodimer.

  • Reabsorption of neutral Amino Acids mediated by Amino Acid Transporter LAT2 and TAT1 in the basolateral membrane of proximal tubule.
    Archives of pharmacal research, 2005
    Co-Authors: Sun Young Park, Yoshikatsu Kanai, Arthit Chairoungdua, In Jin Kim, Bong Kyu Choi, Jong-keun Kim, Kyung Jin Park, Kyu Yong Jung, Seoul Lee, Hitoshi Endou
    Abstract:

    In order to understand the renal reabsorption mechanism of neutral Amino Acids via Amino Acid Transporters, we have isolated human L-type Amino Acid Transporter 2 (hLAT2) and human T-type Amino Acid Transporter 1 (hTAT1) in human, then, we have examined and compared the gene structures, the functional characterizations and the localization in human kidney. Northern blot analysis showed that hLAT2 mRNA was expressed at high levels in the heart, brain, placenta, kidney, spleen, prostate, testis, ovary, lymph node and the fetal liver. The hTAT1 mRNA was detected at high levels in the heart, placenta, liver, skeletal muscle, kidney, pancreas, spleen, thymus and prostate. Immunohistochemical analysis on the human kidney revealed that the hLAT2 and hTAT1 proteins coexist in the basolateral membrane of the renal proximal tubules. The hLAT2 transports all neutral Amino Acids and hTAT1 transports aromatic Amino Acids. The basolateral location of the hLAT2 and hTAT1 proteins in the renal proximal tubule as well as the Amino Acid transport activity of hLAT2 and hTAT1 suggests that these Transporters contribute to the renal reabsorption of neutral and aromatic Amino Acids in the basolateral domain of epithelial proximal tubule cells, respectively. Therefore, LAT2 and TAT1 play essential roles in the reabsorption of neutral Amino Acids from the epithelial cells to the blood stream in the kidney. Because LAT2 and TAT1 are essential to the efficient absorption of neutral Amino Acids from the kidney, their defects might be involved in the pathogenesis of disorders caused by a disruption in Amino Acid absorption such as blue diaper syndrome.

  • Identification and Characterization of a Novel Member of the Heterodimeric Amino Acid Transporter Family Presumed to be Associated with an Unknown Heavy Chain
    The Journal of biological chemistry, 2001
    Co-Authors: Arthit Chairoungdua, Yoshikatsu Kanai, Hirotaka Matsuo, Kyung Kim, Jun Inatomi, Hitoshi Endou
    Abstract:

    Abstract We identified a novel Amino Acid Transporter designated Asc-2 (for asc-type Amino Acid Transporter 2). Asc-2 exhibited relatively low but significant sequence similarity to the members of the heterodimeric Amino Acid Transporters. The cysteine residue responsible for the disulfide bond formation between Transporters (light chains) and heavy chain subunits in the heterodimeric Amino Acid Transporters is conserved for Asc-2. Asc-2 is, however, not colocalized with the already known heavy chains such as 4F2 heavy chain (4F2hc) or related to b0,+ Amino Acid Transporter (rBAT) in mouse kidney. Because Asc-2 solely expressed or coexpressed with 4F2hc or rBAT did not induce functional activity, we generated fusion proteins in which Asc-2 is connected with 4F2hc or rBAT. The fusion proteins were sorted to the plasma membrane and expressed the function corresponding to the Na+-independent small neutral Amino Acid transport system asc. Distinct from the already identified system asc Transporter Asc-1 which is associated with 4F2hc, Asc-2-mediated transport is less stereoselective and did not accept some of the high affinity substrates of Asc-1 such as α-Aminoisobutyric Acid and β-alanine. Asc-2 message was detected in kidney, placenta, spleen, lung, and skeletal muscle. In kidney, Asc-2 protein was present in the epithelial cells lining collecting ducts. In the Western blot analysis on mouse erythrocytes and kidney, Asc-2 was detected as multiple bands in the nonreducing condition, whereas the bands shifted to a single band at lower molecular weight, suggesting the association of Asc-2 with other protein(s) via a disulfide bond. The finding of Asc-2 would lead to the establishment of a new subgroup of heterodimeric Amino Acid Transporter family which includes Transporters associated not with 4F2hc or rBAT but with other unknown heavy chains.

Arthit Chairoungdua - One of the best experts on this subject based on the ideXlab platform.

  • L-type Amino Acid Transporter-1 expressed in human astrocytomas, U343MGa.
    Biological & pharmaceutical bulletin, 2007
    Co-Authors: Shinji Asano, Arthit Chairoungdua, Hitoshi Endou, Megumi Kameyama, Ayako Oura, Anna Morisato, Hideki Sakai, Yoshiaki Tabuchi, Yoshikatsu Kanai
    Abstract:

    LAT1 (L-type Amino Acid Transporter 1), one of the L-type Amino Acid Transporters, transports the branched and aromatic Amino Acids. LAT1 requires the heavy chain of 4F2 antigen (4F2hc) for the functional expression as an Amino Acid Transporter. The expression of this Transporter is up-regulated in tumor cells and rapidly-growing cells to support their proliferation. Here, we studied the expression of LAT1 and 4F2hc in human cultured cells by real-time PCR and Western blot, and found that human brain astrocytomas, U343MGa, highly expressed LAT1 and 4F2hc mRNAs and proteins. The uptake of [14C]leucine by U343MGa cells is Na+-independent and inhibited by BCH (2-Amino-2-norbornane carboxylic Acid), and branched and aromatic Amino Acids, indicating that the LAT1 is expressed at the cell surface. Pulse chase labeling and surface labeling experiments of this cell line indicate that the protein synthesis of LAT1 and 4F2hc is slow, however, the heterodimeric complex assembled in the cells is very stable, and that the disulfide bond between the LAT1 and 4F2hc is not directly involved in the stability of the heterodimer.

  • Reabsorption of neutral Amino Acids mediated by Amino Acid Transporter LAT2 and TAT1 in the basolateral membrane of proximal tubule.
    Archives of pharmacal research, 2005
    Co-Authors: Sun Young Park, Yoshikatsu Kanai, Arthit Chairoungdua, In Jin Kim, Bong Kyu Choi, Jong-keun Kim, Kyung Jin Park, Kyu Yong Jung, Seoul Lee, Hitoshi Endou
    Abstract:

    In order to understand the renal reabsorption mechanism of neutral Amino Acids via Amino Acid Transporters, we have isolated human L-type Amino Acid Transporter 2 (hLAT2) and human T-type Amino Acid Transporter 1 (hTAT1) in human, then, we have examined and compared the gene structures, the functional characterizations and the localization in human kidney. Northern blot analysis showed that hLAT2 mRNA was expressed at high levels in the heart, brain, placenta, kidney, spleen, prostate, testis, ovary, lymph node and the fetal liver. The hTAT1 mRNA was detected at high levels in the heart, placenta, liver, skeletal muscle, kidney, pancreas, spleen, thymus and prostate. Immunohistochemical analysis on the human kidney revealed that the hLAT2 and hTAT1 proteins coexist in the basolateral membrane of the renal proximal tubules. The hLAT2 transports all neutral Amino Acids and hTAT1 transports aromatic Amino Acids. The basolateral location of the hLAT2 and hTAT1 proteins in the renal proximal tubule as well as the Amino Acid transport activity of hLAT2 and hTAT1 suggests that these Transporters contribute to the renal reabsorption of neutral and aromatic Amino Acids in the basolateral domain of epithelial proximal tubule cells, respectively. Therefore, LAT2 and TAT1 play essential roles in the reabsorption of neutral Amino Acids from the epithelial cells to the blood stream in the kidney. Because LAT2 and TAT1 are essential to the efficient absorption of neutral Amino Acids from the kidney, their defects might be involved in the pathogenesis of disorders caused by a disruption in Amino Acid absorption such as blue diaper syndrome.

  • identification of a novel system l Amino Acid Transporter structurally distinct from heterodimeric Amino Acid Transporters
    Journal of Biological Chemistry, 2003
    Co-Authors: Ellappan Babu, Yoshikatsu Kanai, Arthit Chairoungdua, Do Kyung Kim, Yuji Iribe, Sahatchai Tangtrongsup, Promsuk Jutabha, Nesar Ahmed, Shinichi Sakamoto
    Abstract:

    A cDNA that encodes a novel Na+-independent neutral Amino Acid Transporter was isolated from FLC4 human hepatocarcinoma cells by expression cloning. When expressed in Xenopus oocytes, the encoded protein designated LAT3 (L-type Amino Acid Transporter 3) transported neutral Amino Acids such as l-leucine, l-isoleucine, l-valine, and l-phenylalanine. The LAT3-mediated transport was Na+-independent and inhibited by 2-Aminobicyclo[2.2.1]heptane-2-carboxylic Acid, consistent with the properties of system L. Distinct from already known system L Transporters LAT1 and LAT2, which form heterodimeric complex with 4F2 heavy chain, LAT3 was functional by itself in Xenopus oocytes. The deduced Amino Acid sequence of LAT3 was identical to the gene product of POV1 reported as a prostate cancer-up-regulated gene whose function was not determined, whereas it did not exhibit significant similarity to already identified Transporters. The Eadie-Hofstee plots of LAT3-mediated transport were curvilinear, whereas the low affinity component is predominant at physiological plasma Amino Acid concentration. In addition to Amino Acid substrates, LAT3 recognized Amino Acid alcohols. The transport of l-leucine was electroneutral and mediated by a facilitated diffusion. In contrast, l-leucinol, l-valinol, and l-phenylalaninol, which have a net positive charge induced inward currents under voltage clamp, suggesting these compounds are transported by LAT3. LAT3-mediated transport was inhibited by the pretreatment with N-ethylmaleimide, consistent with the property of system L2 originally characterized in hepatocyte primary culture. Based on the substrate selectivity, affinity, and N-ethylmaleimide sensitivity, LAT3 is proposed to be a Transporter subserving system L2. LAT3 should denote a new family of organic solute Transporters.

  • Identification of a novel Na+-independent Acidic Amino Acid Transporter with structural similarity to the member of a heterodimeric Amino Acid Transporter family associated with unknown heavy chains.
    The Journal of biological chemistry, 2002
    Co-Authors: Hirotaka Matsuo, Yoshikatsu Kanai, Arthit Chairoungdua, Ju Young Kim, Kyung Kim, Jun Inatomi, Yasuhiro Shigeta, Hisako Ishimine, Sophapun Chaekuntode, Kittipong Tachampa
    Abstract:

    Abstract We identified a novel Na+-independent Acidic Amino Acid Transporter designated AGT1 (aspartate/glutamateTransporter 1). AGT1 exhibits the highest sequence similarity (48% identity) to the Na+-independent small neutral Amino Acid Transporter Asc (asc-type Amino Acid Transporter)-2 a member of the heterodimeric Amino Acid Transporter family presumed to be associated with unknown heavy chains (Chairoungdua, A., Kanai, Y., Matsuo, H., Inatomi, J., Kim, D. K., and Endou, H. (2001) J. Biol. Chem. 276, 49390–49399). The cysteine residue responsible for the disulfide bond formation between Transporters (light chains) and heavy chain subunits of the heterodimeric Amino Acid Transporter family is conserved for AGT1. Because AGT1 solely expressed or coexpressed with already known heavy chain 4F2hc (4F2 heavy chain) or rBAT (related tob 0,+-Amino AcidTransporter) did not induce functional activity, we generated fusion proteins in which AGT1 was connected with 4F2hc or rBAT. The fusion proteins were sorted to the plasma membrane and expressed the Na+-independent transport activity for Acidic Amino Acids. Distinct from the Na+-independent cystine/glutamate Transporter xCT structurally related to AGT1, AGT1 did not accept cystine, homocysteate, andl-α-Aminoadipate and exhibited high affinity to aspartate as well as glutamate, suggesting that the negative charge recognition site in the side chain-binding site of AGT1 would be closer to the α-carbon binding site compared with that of xCT. The AGT1 message was predominantly expressed in kidney. In mouse kidney, AGT1 protein was present in the basolateral membrane of the proximal straight tubules and distal convoluted tubules. In the Western blot analysis, AGT1 was detected as a high molecular mass band in the nonreducing condition, whereas the band shifted to a 40-kDa band corresponding to the AGT1 monomer in the reducing condition, suggesting the association of AGT1 with other protein via a disulfide bond. The finding of AGT1 and Asc-2 has established a new subgroup of the heterodimeric Amino Acid Transporter family whose members associate not with 4F2hc or rBAT but with other unknown heavy chains.

  • Identification and Characterization of a Novel Member of the Heterodimeric Amino Acid Transporter Family Presumed to be Associated with an Unknown Heavy Chain
    The Journal of biological chemistry, 2001
    Co-Authors: Arthit Chairoungdua, Yoshikatsu Kanai, Hirotaka Matsuo, Kyung Kim, Jun Inatomi, Hitoshi Endou
    Abstract:

    Abstract We identified a novel Amino Acid Transporter designated Asc-2 (for asc-type Amino Acid Transporter 2). Asc-2 exhibited relatively low but significant sequence similarity to the members of the heterodimeric Amino Acid Transporters. The cysteine residue responsible for the disulfide bond formation between Transporters (light chains) and heavy chain subunits in the heterodimeric Amino Acid Transporters is conserved for Asc-2. Asc-2 is, however, not colocalized with the already known heavy chains such as 4F2 heavy chain (4F2hc) or related to b0,+ Amino Acid Transporter (rBAT) in mouse kidney. Because Asc-2 solely expressed or coexpressed with 4F2hc or rBAT did not induce functional activity, we generated fusion proteins in which Asc-2 is connected with 4F2hc or rBAT. The fusion proteins were sorted to the plasma membrane and expressed the function corresponding to the Na+-independent small neutral Amino Acid transport system asc. Distinct from the already identified system asc Transporter Asc-1 which is associated with 4F2hc, Asc-2-mediated transport is less stereoselective and did not accept some of the high affinity substrates of Asc-1 such as α-Aminoisobutyric Acid and β-alanine. Asc-2 message was detected in kidney, placenta, spleen, lung, and skeletal muscle. In kidney, Asc-2 protein was present in the epithelial cells lining collecting ducts. In the Western blot analysis on mouse erythrocytes and kidney, Asc-2 was detected as multiple bands in the nonreducing condition, whereas the bands shifted to a single band at lower molecular weight, suggesting the association of Asc-2 with other protein(s) via a disulfide bond. The finding of Asc-2 would lead to the establishment of a new subgroup of heterodimeric Amino Acid Transporter family which includes Transporters associated not with 4F2hc or rBAT but with other unknown heavy chains.

Hirotaka Matsuo - One of the best experts on this subject based on the ideXlab platform.

  • Identification of a novel Na+-independent Acidic Amino Acid Transporter with structural similarity to the member of a heterodimeric Amino Acid Transporter family associated with unknown heavy chains.
    The Journal of biological chemistry, 2002
    Co-Authors: Hirotaka Matsuo, Yoshikatsu Kanai, Arthit Chairoungdua, Ju Young Kim, Kyung Kim, Jun Inatomi, Yasuhiro Shigeta, Hisako Ishimine, Sophapun Chaekuntode, Kittipong Tachampa
    Abstract:

    Abstract We identified a novel Na+-independent Acidic Amino Acid Transporter designated AGT1 (aspartate/glutamateTransporter 1). AGT1 exhibits the highest sequence similarity (48% identity) to the Na+-independent small neutral Amino Acid Transporter Asc (asc-type Amino Acid Transporter)-2 a member of the heterodimeric Amino Acid Transporter family presumed to be associated with unknown heavy chains (Chairoungdua, A., Kanai, Y., Matsuo, H., Inatomi, J., Kim, D. K., and Endou, H. (2001) J. Biol. Chem. 276, 49390–49399). The cysteine residue responsible for the disulfide bond formation between Transporters (light chains) and heavy chain subunits of the heterodimeric Amino Acid Transporter family is conserved for AGT1. Because AGT1 solely expressed or coexpressed with already known heavy chain 4F2hc (4F2 heavy chain) or rBAT (related tob 0,+-Amino AcidTransporter) did not induce functional activity, we generated fusion proteins in which AGT1 was connected with 4F2hc or rBAT. The fusion proteins were sorted to the plasma membrane and expressed the Na+-independent transport activity for Acidic Amino Acids. Distinct from the Na+-independent cystine/glutamate Transporter xCT structurally related to AGT1, AGT1 did not accept cystine, homocysteate, andl-α-Aminoadipate and exhibited high affinity to aspartate as well as glutamate, suggesting that the negative charge recognition site in the side chain-binding site of AGT1 would be closer to the α-carbon binding site compared with that of xCT. The AGT1 message was predominantly expressed in kidney. In mouse kidney, AGT1 protein was present in the basolateral membrane of the proximal straight tubules and distal convoluted tubules. In the Western blot analysis, AGT1 was detected as a high molecular mass band in the nonreducing condition, whereas the band shifted to a 40-kDa band corresponding to the AGT1 monomer in the reducing condition, suggesting the association of AGT1 with other protein via a disulfide bond. The finding of AGT1 and Asc-2 has established a new subgroup of the heterodimeric Amino Acid Transporter family whose members associate not with 4F2hc or rBAT but with other unknown heavy chains.

  • Identification and Characterization of a Novel Member of the Heterodimeric Amino Acid Transporter Family Presumed to be Associated with an Unknown Heavy Chain
    The Journal of biological chemistry, 2001
    Co-Authors: Arthit Chairoungdua, Yoshikatsu Kanai, Hirotaka Matsuo, Kyung Kim, Jun Inatomi, Hitoshi Endou
    Abstract:

    Abstract We identified a novel Amino Acid Transporter designated Asc-2 (for asc-type Amino Acid Transporter 2). Asc-2 exhibited relatively low but significant sequence similarity to the members of the heterodimeric Amino Acid Transporters. The cysteine residue responsible for the disulfide bond formation between Transporters (light chains) and heavy chain subunits in the heterodimeric Amino Acid Transporters is conserved for Asc-2. Asc-2 is, however, not colocalized with the already known heavy chains such as 4F2 heavy chain (4F2hc) or related to b0,+ Amino Acid Transporter (rBAT) in mouse kidney. Because Asc-2 solely expressed or coexpressed with 4F2hc or rBAT did not induce functional activity, we generated fusion proteins in which Asc-2 is connected with 4F2hc or rBAT. The fusion proteins were sorted to the plasma membrane and expressed the function corresponding to the Na+-independent small neutral Amino Acid transport system asc. Distinct from the already identified system asc Transporter Asc-1 which is associated with 4F2hc, Asc-2-mediated transport is less stereoselective and did not accept some of the high affinity substrates of Asc-1 such as α-Aminoisobutyric Acid and β-alanine. Asc-2 message was detected in kidney, placenta, spleen, lung, and skeletal muscle. In kidney, Asc-2 protein was present in the epithelial cells lining collecting ducts. In the Western blot analysis on mouse erythrocytes and kidney, Asc-2 was detected as multiple bands in the nonreducing condition, whereas the bands shifted to a single band at lower molecular weight, suggesting the association of Asc-2 with other protein(s) via a disulfide bond. The finding of Asc-2 would lead to the establishment of a new subgroup of heterodimeric Amino Acid Transporter family which includes Transporters associated not with 4F2hc or rBAT but with other unknown heavy chains.

  • expression cloning of a na independent aromatic Amino Acid Transporter with structural similarity to h monocarboxylate Transporters
    Journal of Biological Chemistry, 2001
    Co-Authors: Yoshikatsu Kanai, Arthit Chairoungdua, Hirotaka Matsuo, Hitoshi Endou
    Abstract:

    Abstract A cDNA was isolated from rat small intestine by expression cloning which encodes a novel Na+-independent Transporter for aromatic Amino Acids. When expressed in Xenopus oocytes, the encoded protein designated as TAT1 (T-type Amino Acid Transporter 1) exhibited Na+-independent and low-affinity transport of aromatic Amino Acids such as tryptophan, tyrosine, and phenylalanine (K m values: ∼5 mm), consistent with the properties of classical Amino Acid transport system T. TAT1 accepted some variations of aromatic side chains because it interacted with Amino Acid-related compounds such as l-DOPA and 3-O-methyl-DOPA. Because TAT1 acceptedN-methyl- and N-acetyl-derivatives of aromatic Amino Acids but did not accept their methylesters, it is proposed that TAT1 recognizes Amino Acid substrates as anions. Consistent with this, TAT1 exhibited sequence similarity (∼30% identity at the Amino Acid level) to H+/monocarboxylate Transporters. Distinct from H+/monocarboxylate Transporters, however, TAT1 was not coupled with the H+ transport but it mediated an electroneutral facilitated diffusion. TAT1 mRNA was strongly expressed in intestine, placenta, and liver. In rat small intestine TAT1 immunoreactivity was detected in the basolateral membrane of the epithelial cells suggesting its role in the transepithelial transport of aromatic Amino Acids. The identification of the Amino Acid Transporter with distinct structural and functional characteristics will not only facilitate the expansion of Amino Acid Transporter families but also provide new insights into the mechanisms of substrate recognition of organic solute Transporters.

  • identification and characterization of a na independent neutral Amino Acid Transporter that associates with the 4f2 heavy chain and exhibits substrate selectivity for small neutral d and l Amino Acids
    Journal of Biological Chemistry, 2000
    Co-Authors: Yoshiki Fukasawa, Arthit Chairoungdua, Hirotaka Matsuo, Ju Young Kim, Hiroko Segawa, Do Kyung Kim, Seok Ho Cha, Hitoshi Endou
    Abstract:

    Abstract A cDNA was isolated from the mouse brain that encodes a novel Na+-independent neutral Amino Acid Transporter. The encoded protein, designated as Asc-1 (asc-type Amino Acid Transporter 1), was found to be structurally related to recently identified mammalian Amino Acid Transporters for the transport systems L, y+L, xC −, and b0,+, which are linked, via a disulfide bond, to the type II membrane glycoproteins, 4F2 heavy chain (4F2hc), or rBAT (related to b0,+ Amino Acid Transporter). Asc-1 required 4F2hc for its functional expression. In Western blot analysis in the nonreducing condition, a 118-kDa band, which seems to correspond to the heterodimeric complex of Asc-1 and 4F2hc, was detected in the mouse brain. The band shifted to 33 kDa in the reducing condition, confirming that Asc-1 and 4F2hc are linked via a disulfide bond. Asc-1-mediated transport was not dependent on the presence of Na+ or Cl−. Although Asc-1 showed a high sequence homology (66% identity at the Amino Acid level) to the Na+-independent broad scope neutral Amino Acid Transporter LAT2 (Segawa, H., Fukasawa, Y., Miyamoto, K., Takeda, E., Endou, H., and Kanai, Y. (1999)J. Biol. Chem. 274, 19745–19751), Asc-1 also exhibited distinctive substrate selectivity and transport properties. Asc-1 preferred small neutral Amino Acids such as Gly,l-Ala, l-Ser, l-Thr, andl-Cys, and α-Aminoisobutyric Acid as substrates. Asc-1 also transported d-isomers of the small neutral Amino Acids, in particular d-Ser, a putative endogenous modulator of N-methyl-d-aspartate-type glutamate receptors, with high affinity. Asc-1 operated preferentially, although not exclusively, in an exchange mode. Asc-1 mRNA was detected in the brain, lung, small intestine, and placenta. The functional properties of Asc-1 seem to be consistent with those of a Transporter subserving the Na+-independent small neutral Amino Acid transport system asc.

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  • Expression of Amino Acid Transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma
    Human pathology, 2018
    Co-Authors: Kyoichi Kaira, Osamu Kawashima, Hedeki Endoh, Kazuyoshi Imaizumi, Yasuhiro Goto, Mitsuhiro Kamiyoshihara, Masayuki Sugano, Ryohei Yamamoto, Takashi Osaki, Shigefumi Tanaka
    Abstract:

    Amino Acid Transporters are necessary for tumor growth, metastasis, and survival of various neoplasms; however, the clinicopathological significance of L-type Amino Acid Transporter 1 (LAT1) and 4F2 cell surface antigen (4F2hc) in patients with pulmonary pleomorphic carcinoma (PPC) remainsunknown. The aim of this study is to clarify the prognostic impact of these Amino Acid Transporters in PPC. One hundred five patients with surgically resected PPC were assessed by immunohistochemistry. The expression of LAT1 and 4F2hc, and Ki-67 labeling index were investigated using specimens of the resected tumors. LAT1 and 4F2hc were highly expressed in 35% and 53% of all patients (n = 105, P < .01), 25% and 48% of patients with an adenocarcinoma component (n = 48, P = .02), and 44% and 58% of patients with a nonadenocarcinoma component (n = 57, P = .18), respectively. A high LAT1 expression was significantly related to advanced disease, lymphatic permeation, tumor cell proliferation, and 4F2hc expression. By multivariate analysis, LAT1 and 4F2hc were identified as significant independent markers for predicting a worse prognosis. LAT1 is highly expressed in PPC, and high LAT1 expression can serve as a significant predictor linked to a worse prognosis in patients with PPC.

  • prognostic significance of Amino Acid Transporter expression lat1 asct2 and xct in surgically resected tongue cancer
    British Journal of Cancer, 2014
    Co-Authors: Minoru Toyoda, Kyoichi Kaira, Noriko S Ishioka, Hideyuki Tominaga, Yasuhiro Ohshima, Masato Shino, Koichi Sakakura, Yukihiro Takayasu, Kengo Takahashi, Noboru Oriuchi
    Abstract:

    Amino-Acid Transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type Amino-Acid Transporter 1 (LAT1), system ASC Amino-Acid Transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these Amino-Acid Transporters in tongue cancer. Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. L-type Amino-Acid Transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC Amino-Acid Transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. L-type Amino-Acid Transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.

  • asc Amino Acid Transporter 2 asct2 as a novel prognostic marker in non small cell lung cancer
    British Journal of Cancer, 2014
    Co-Authors: Kimihiro Shimizu, Noriaki Sunaga, Kyoichi Kaira, Hideyuki Tominaga, Noboru Oriuchi, Yoshikatsu Kanai, Shushi Nagamori, Yoshio Tomizawa, Osamu Kawashima, Masanobu Yamada
    Abstract:

    ASC Amino-Acid Transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer

  • clinical significance of l type Amino Acid Transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer
    BMC Cancer, 2013
    Co-Authors: Kyoichi Kaira, Kazuhisa Arakawa, Yutaka Sunose, Noriaki Sunaga, Tetsushi Ogawa, Noriko S Ishioka, Hideyuki Tominaga, Kimihiro Shimizu, Yasuhiro Ohshima, Noboru Oriuchi
    Abstract:

    Background The expression of L-type Amino Acid Transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer.

  • prognostic significance of l type Amino Acid Transporter 1 expression in surgically resected pancreatic cancer
    British Journal of Cancer, 2012
    Co-Authors: Kyoichi Kaira, Kazuhisa Arakawa, Yutaka Sunose, Noriaki Sunaga, Tetsushi Ogawa, Hideyuki Tominaga, Noboru Oriuchi, Kimihiro Shimizu, Hideaki Itoh, Shushi Nagamori
    Abstract:

    Prognostic significance of L-type Amino-Acid Transporter 1 expression in surgically resected pancreatic cancer