Distinct Domains of CD98hc Regulate Integrins and Amino Acid Transport

Abstract

CD98 is a cell surface heterodimer formed by the covalent linkage of CD98 heavy chain (CD98hc) with several different light chains to form amino acid transporters. CD98hc also binds specifically to the integrin ␤ 1A cytoplasmic domain and regulates integrin function. In this study, we examined the relationship between the ability of CD98hc to stimulate amino acid transport and to affect integrin function. By constructing chimeras with CD98hc and a type II transmembrane protein (CD69), we found that the cytoplasmic and transmembrane domains of CD98hc are required for its effects on integrin function, while the extracellular domain is required for stimulation of isoleucine transport. Consequently, the capacity to promote amino acid transport is not required for CD98hc's effect on integrin function. Furthermore, a mutant of CD98hc that lacks its integrin binding site can still promote increased isoleucine transport. Thus, these two functions of CD98hc are separable and require distinct domains of the protein.

Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes

“…Particularly conspicuous is the block encompassing positions 102-124, which in the human sequence has been identified as the TM domain. This location of the domain suggests that the N terminus of the protein is located intracellularly and the C terminus extracellularly, as has been demonstrated for the human CD98 heavy chain (30). Hence the chain is a type II protein.…”

Solute carrier family 3 member 2 (Slc3a2) controls yolk syncytial layer (YSL) formation by regulating microtubule networks in the zebrafish embryo

“…Zebrafish solute carrier family 3 member 2 (Slc3a2) proteins have about 60% sequence identity to the mammalian Slc3a2/4F2hc/ CD98 heavy chain (CD98hc), an 85-kDa glycosylated type II membrane protein, with conservation in intracellular, transmembrane, and extracellular domains. Mammalian Slc3a2/4F2hc/ CD98hc binds to integrin β1 and β3 subunits through its intracellular domain and hence is involved in various integrin-mediated functions independent of the CD98 light chain (18)(19)(20)(21)(22). Mammalian Slc3a2/4F2hc/CD98hc regulates integrin-mediated cell spreading, cell migration, and adhesion in mouse embryonic stem cells (19) and human placenta trophoblasts (21).…”

Structural bases for the interaction and stabilization of the human amino acid transporter LAT2 with its ancillary protein 4F2hc

“…In contrast, 4F2hc and rBAT are necessary for heterodimerization and functional expression of light subunits at the cell surface when expressed in Xenopus oocytes and mammalian cells (1). Specifically, 4F2hc-ED is necessary for these functions (9,10). Desolvation of hydrophobic residues might be extended to the recognition of other light subunits by 4F2hc.…”

“…The conserved cysteine residue participating in the intersubunit disulfide bridge is located between the single TMD and 4F2hc-ED. Physical and functional interaction of 4F2hc with integrins has been mapped to the TMD and cytosolic N-terminal domain (7,9), whereas 4F2hc-ED is necessary for functional heterodimerization with the light subunit (9,10). The light subunits are nonglycosylated proteins and have a 12-TMD topology with intracellular N and C termini (1).…”