Papers by Laura Rodriguez de la Ballina
CD98hc functions as an amino acid (AA) transporter (together with another subunit) and integrin s... more CD98hc functions as an amino acid (AA) transporter (together with another subunit) and integrin signaling en-hancer. It is overexpressed in highly proliferative cells in both physiological and pathological conditions. CD98hc deletion induces strong impairment of cell proliferation in vivo and in vitro. Here, we investigate CD98hc-associated AA transport in cell survival and proliferation. By using chimeric versions of CD98hc, the two functions of the protein can be uncoupled. Although recovering the CD98hc AA transport capacity restores the in vivo and in vitro proliferation of CD98hc-null cells, reconstitution of the integrin signaling function of CD98hc is unable to restore in vitro proliferation of those cells. CD98hc-associated transporters (i.e. xCT, LAT1, and y LAT2 in wild-type cells) are crucial to control reactive oxygen species and intracellular AA levels, thus sustaining cell survival and proliferation. Moreover, in CD98hc-null cells the deficiency of CD98hc/xCT cannot be compensated, leading to cell death by ferroptosis. Supplementation of culture media with-mercap-toethanol rescues CD98hc-deficient cell survival. Under such conditions null cells show oxidative stress and intracellular AA imbalance and, consequently, limited proliferation. CD98hc-null cells also present reduced intracellular levels of branched-chain and aromatic amino acids (BCAAs and ARO AAs, respectively) and induced expression of peptide transporter 1 (PEPT1). Interestingly, external supply of dipeptides containing BCAAs and ARO AAs rescues cell proliferation and compensates for impaired uptake of CD98hc/LAT1 and CD98hc/ y LAT2. Our data establish CD98hc as a master protective gene at the crossroad of redox control and AA availability, making it a relevant therapeutic target in cancer. Proliferative cells have an increased demand for nutrients such as glucose, AAs, 8 fatty acids, and vitamins. Heteromeric amino acid transporters are among several families of solute carriers (SLC Tables website) that mediate the influx or efflux of solutes (AAs among others) through the plasma membrane of mammalian cells. Heteromeric amino acid transporters are composed of a heavy (SLC3 family) and a light (L-type amino acid transporters (LATs) from SLC7 family) subunit, linked by a disulfide bridge (1). The heavy chain carries the complex to the plasma membrane (2), whereas the light chain constitutes
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The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a ... more The CD98/LAT1 complex is overexpressed in aggressive human cancers and is thereby described as a potential therapeutic target.
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4F2hc (CD98hc) is a multifunctional type II membrane glyco-protein involved in amino acid transpo... more 4F2hc (CD98hc) is a multifunctional type II membrane glyco-protein involved in amino acid transport and cell fusion, adhesion , and transformation. The structure of the ectodomain of human 4F2hc has been solved using monoclinic (Protein Data Bank code 2DH2) and orthorhombic (Protein Data Bank code 2DH3) crystal forms at 2.1 and 2.8 A ˚ , respectively. It is composed of a () 8 barrel and an antiparallel 8 sandwich related to bacterial-glycosidases, although lacking key catalytic residues and consequently catalytic activity. 2DH3 is a dimer with Zn 2 coordination at the interface. Human 4F2hc expressed in several cell types resulted in cell surface and Cys 109 disulfide bridge-linked homodimers with major architectural features of the crystal dimer, as demonstrated by cross-linking experiments. 4F2hc has no significant hydrophobic patches at the surface. Monomer and homodimer have a polarized charged surface. The N terminus of the solved structure, including the position of Cys 109 residue located four residues apart from the transmembrane domain, is adjacent to the positive face of the ectodomain. This location of the N terminus and the Cys 109-intervening disulfide bridge imposes space restrictions sufficient to support a model for electrostatic interaction of the 4F2hc ectodomain with membrane phospholipids. These results provide the first crystal structure of heteromeric amino acid transporters and suggest a dynamic interaction of the 4F2hc ectodomain with the plasma membrane.
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Papers by Laura Rodriguez de la Ballina