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REVIEW
Eunsun Park, Hyesung Kim, Seokho Yoon, Bogun Jang
The glycoprotein CD98, or CD98 heavy chain (CD98hc), encoded by the SLC3A2 gene, plays a crucial role in cancer development and progression. CD98hc, forming heterodimeric complexes with various light chains, regulates neutral amino acid transport across cell membranes. The intricate interplay between CD98hc, integrins, and amino acid transporters shapes the tumor microenvironment and contributes to tumor growth. Elevated expression of CD98hc in various cancers correlates with poor prognosis, making it a potential prognostic marker...
April 16, 2024: Histology and Histopathology
#2
JOURNAL ARTICLE
Josep Rullo-Tubau, Maria Martinez-Molledo, Paola Bartoccioni, Ignasi Puch-Giner, Ángela Arias, Suwipa Saen-Oon, Camille Stephan-Otto Attolini, Rafael Artuch, Lucía Díaz, Víctor Guallar, Ekaitz Errasti-Murugarren, Manuel Palacín, Oscar Llorca
Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion...
April 6, 2024: Nature Communications
#3
Praveen Agrawal, Shuhui Chen, Ana de Pablos, Faezeh Jame-Chenarboo, Eleazar Miera Saenz de Vega, Farbod Darvishian, Iman Osman, Amaia Lujambio, Lara K Mahal, Eva Hernando
Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that α-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding α-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro ...
March 12, 2024: bioRxiv
#4
JOURNAL ARTICLE
Yohei Kawasaki, Yasufumi Omori, Shinsuke Suzuki, Takechiyo Yamada
INTRODUCTION: The prognosis of head and neck squamous cell carcinoma (HNSCC) is generally good in cases of high radiation sensitivity but poor in cases exhibiting radiation resistance; this resistance has been attributed to the presence of cancer stem cells. In recent years, CD98hc overexpression has been associated with poor prognosis in various types of cancers. CD98 is a heterodimer of heavy and light chains and is strongly involved in cell proliferation, survival, migration, and adhesion...
2023: Archives of Medical Science: AMS
#5
JOURNAL ARTICLE
Ghasidit Pornnoppadol, Layne G Bond, Michael J Lucas, Jennifer M Zupancic, Yun-Huai Kuo, Boya Zhang, Colin F Greineder, Peter M Tessier
The inability of antibodies to penetrate the blood-brain barrier (BBB) is a key limitation to their use in diverse applications. One promising strategy is to deliver IgGs using a bispecific BBB shuttle, which involves fusing an IgG to a second affinity ligand that engages a cerebrovascular endothelial target and facilitates transport across the BBB. Nearly all prior efforts have focused on shuttles that target transferrin receptor (TfR-1) despite inherent delivery and safety challenges. Here, we report bispecific antibody shuttles that engage CD98hc, the heavy chain of the large neutral amino acid transporter (LAT1), and efficiently transport IgGs into the brain...
October 10, 2023: Cell Chemical Biology
#6
REVIEW
Pu Xia, Anna Dubrovska
The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y+ LAT1 (SLC7A7), y+ LAT2 (SLC7A6), xCT (SLC7A11) and Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake...
2023: Frontiers in Oncology
#7
Kylie S Chew, Robert C Wells, Arash Moshkforoush, Darren Chan, Kendra J Lechtenberg, Hai L Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B Srivastava, Raymond K Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K Earr, Audrey Gill, David Huynh, David Joy, Kristen N Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W Lexa, Nicholas P D Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N Nguyen, Edwin I Lozano, Michelle E Pizzo, Elysia Roche, Patricia Sacayon, Meredith E K Calvert, Richard Daneman, Mark S Dennis, Joseph Duque, Kapil Gadkar, Joseph W Lewcock, Cathal S Mahon, René Meisner, Hilda Solanoy, Robert G Thorne, Ryan J Watts, Y Joy Yu Zuchero, Mihalis S Kariolis
No abstract text is available yet for this article.
September 7, 2023: Nature Communications
#8
JOURNAL ARTICLE
Kylie S Chew, Robert C Wells, Arash Moshkforoush, Darren Chan, Kendra J Lechtenberg, Hai L Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B Srivastava, Raymond K Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K Earr, Audrey Gill, David Huynh, David Joy, Kristen N Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W Lexa, Nicholas P D Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N Nguyen, Edwin I Lozano, Michelle E Pizzo, Elysia Roche, Patricia Sacayon, Meredith E K Calvert, Richard Daneman, Mark S Dennis, Joseph Duque, Kapil Gadkar, Joseph W Lewcock, Cathal S Mahon, René Meisner, Hilda Solanoy, Robert G Thorne, Ryan J Watts, Y Joy Yu Zuchero, Mihalis S Kariolis
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc ). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc ) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties...
August 19, 2023: Nature Communications
#9
JOURNAL ARTICLE
Juan Carlos Montero, Sofía Del Carmen, Mar Abad, José M Sayagués, Antonio Barbáchano, Asunción Fernández-Barral, Alberto Muñoz, Atanasio Pandiella
BACKGROUND: Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc. METHODS: Western blot and immunohistochemical analyses of CD98hc protein expression were carried out on paired normal and tumoral tissues from patients with CRC. Immunofluorescence and western studies were used to characterize the action of a DM1-based CD98hc-directed antibody-drug conjugate (ADC)...
August 9, 2023: Journal of Experimental & Clinical Cancer Research: CR
#10
JOURNAL ARTICLE
Naoki Hosen
CAR-T cell therapy is a twenty-first-century immunotherapy breakthrough. Another breakthrough in immunotherapy is checkpoint antibody therapy, which can treat multiple cancers with a single antibody, whereas CAR-T cell therapy requires an appropriate target for each cancer type. Other than B-cell malignancies, no good target antigen for cancers has been discovered. We have been working on the development of CAR-T cells that target differences in post-translational changes such as conformation or glycosylation, between cancer and normal cells rather than differences in protein expression levels...
2023: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
#11
Ghasidit Pornnoppadol, Layne G Bond, Michael J Lucas, Jennifer M Zupancic, Yun-Huai Kuo, Boya Zhang, Colin F Greineder, Peter M Tessier
The inability of antibodies and other biologics to penetrate the blood-brain barrier (BBB) is a key limitation to their use in diagnostic, imaging, and therapeutic applications. One promising strategy is to deliver IgGs using a bispecific BBB shuttle, which involves fusing an IgG with a second affinity ligand that engages a cerebrovascular endothelial target and facilitates transport across the BBB. Nearly all prior efforts have focused on the transferrin receptor (TfR-1) as the prototypical endothelial target despite inherent delivery and safety challenges...
April 29, 2023: bioRxiv
#12
Cameron Geller, Joanna Maddela, Ranel Tuplano, Farhana Runa, Yvess Adamian, Robert Güth, Gabriela Ortiz Soto, Luke Tomaneng, Joseph Cantor, Jonathan A Kelber
Extracellular matrix (ECM) protein expression/deposition within and stiffening of the breast cancer microenvironment facilitates disease progression and correlates with poor patient survival. However, the mechanisms by which ECM components control tumorigenic behaviors and responses to therapeutic intervention remain poorly understood. Fibronectin (FN) is a major ECM protein controlling multiple processes. In this regard, we previously reported that DHPS-dependent hypusination of eIF5A1/2 is necessary for fibronectin-mediated breast cancer metastasis and epithelial to mesenchymal transition (EMT)...
April 16, 2023: bioRxiv
#13
JOURNAL ARTICLE
Alice Capuz, Sylvain Osien, Mélodie Anne Karnoub, Soulaimane Aboulouard, Estelle Laurent, Etienne Coyaud, Antonella Raffo-Romero, Marie Duhamel, Amélie Bonnefond, Mehdi Derhourhi, Marco Trerotola, Ikram El Yazidi-Belkoura, David Devos, Monika Zilkova, Firas Kobeissy, Fabien Vanden Abeele, Isabelle Fournier, Dasa Cizkova, Franck Rodet, Michel Salzet
Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells...
April 4, 2023: Cell Death & Disease
#14
JOURNAL ARTICLE
Xin-Yue Zhou, Jin-Yao Li, Jing-Tong Tan, Yi-Li HuangLi, Xiao-Cui Nie, Pu Xia
Ovarian cancer is one of the most common malignant tumours affecting the female reproductive organs. CD147 (BSG) and CD98hc (SLC3A2) are oncogenes that form the CD98hc-CD147 complex, which regulates the proliferation, metastasis, metabolism, and cell cycle of cancer cells. The roles of the CD98hc-CD147 complex in ovarian cancer remain unclear. We analysed the expression and prognostic value of CD147 and CD98hc in ovarian cancer using the TCGA and ICGC databases. The effect of CD147 and CD98hc on the tumour immune response was analysed using the TIMER database...
December 2023: Journal of Obstetrics and Gynaecology: the Journal of the Institute of Obstetrics and Gynaecology
#15
JOURNAL ARTICLE
Ana R Rebelo, Catarina C F Homem
Tumor cells have an increased demand for nutrients to sustain their growth, but how these increased metabolic needs are ensured or how this influences tumor formation and progression remains unclear. To unravel tumor metabolic dependencies, particularly from extracellular metabolites, we have analyzed the role of plasma membrane metabolic transporters in Drosophila brain tumors. Using a well-established neural stem cell-derived tumor model, caused by brat knockdown, we have found that 13 plasma membrane metabolic transporters, including amino acid, carbohydrate and monocarboxylate transporters, are upregulated in tumors and are required for tumor growth...
January 6, 2023: Cellular and Molecular Life Sciences: CMLS
#16
JOURNAL ARTICLE
Joseph P Steiner, Muzna Bachani, Nasir Malik, Catherine DeMarino, Wenxue Li, Kevon Sampson, Myoung-Hwa Lee, Jeffery Kowalak, Manju Bhaskar, Tara Doucet-O'Hare, Marta Garcia-Montojo, Maria Cowen, Bryan Smith, Lauren Bowen Reoma, Julie Medina, Joanna Brunel, Justine Pierquin, Benjamin Charvet, Hervé Perron, Avindra Nath
OBJECTIVE: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env...
October 2022: Annals of Neurology
#17
REVIEW
Sonia Vection, David O'Callaghan, Anne Keriel
The eukaryotic protein CD98hc (also known as 4F2, FRP-1, or SLC3A2) is a membrane glycoprotein and one of the heavy chains of the family of heterodimeric amino acids transporters. It can associate with any of 6 different light chains to form distinct amino acid transporters. CD98hc is also involved in mediation of intracellular integrin signaling. Besides its physiological roles in the development of the placenta and the immune system, CD98hc is important during pathological processes such as tumorigenesis and host-pathogen interaction...
September 2, 2022: FEMS Microbiology Reviews
#18
JOURNAL ARTICLE
Daniela Bianconi, Elisabeth Fabian, Merima Herac, Markus Kieler, Johannes Thaler, Gerald Prager, Matthias Unseld
Background: Cluster of differentiation 98 heavy chain (CD98hc) is a transmembrane protein, which functions both as a coreceptor of ß-integrins, enhancing intracellular integrin-dependent downstream signaling, and as a transporter of branched-chain and aromatic amino acids. As such, it is pivotal in cell cycle regulation and protection of oxidative, nutritional and DNA replication stress. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor clinical prognosis. The role of CD98hc in pancreatic cancer remains to be elucidated...
2022: Journal of Cancer
#19
JOURNAL ARTICLE
Juhyung Lee, Yue Xu, Layla Saidi, Miao Xu, Konrad Zinsmaier, Yihong Ye
Mutations in DNAJC5/CSPα are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent s torage materials (AFSMs) termed lipofuscin. Functionally, DNAJC5 has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how DNAJC5 dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two functionally distinct but coupled chaperoning activities of DNAJC5, which jointly regulate lysosomal homeostasis: While endolysosome-associated DNAJC5 promotes ESCRT-dependent microautophagy, a fraction of perinuclear and non-lysosomal DNAJC5 mediates MAPS...
May 4, 2022: Autophagy
#20
JOURNAL ARTICLE
Ayşe Sedef Köseer, Liliana R Loureiro, Justyna Jureczek, Nicola Mitwasi, Karla Elizabeth González Soto, Julia Aepler, Tabea Bartsch, Anja Feldmann, Leoni A Kunz-Schughart, Annett Linge, Mechthild Krause, Michael Bachmann, Claudia Arndt, Anna Dubrovska
Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e...
March 25, 2022: Cancers
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