Abstract
BackgroundThe multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin β1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. CD98hc-null mice exhibit early post-implantation lethality similar to integrin β1-null mice, supporting the importance of its interaction with integrin β1. On the other hand, the extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. In this respect, CD98hc may also affect development via these transporters.ResultsIn this study, mice were generated from embryonic stem (ES) cell line (PST080) harboring a mutant CD98hc allele (CD98hcΔ/+). Expression of the CD98hc mutant allele results in ΔCD98hc-β geo fusion protein where extracellular C-terminal 102 amino acids of CD98hc are replaced with β geo. Analyses of PST080 ES cells as well as reconstituted frog oocytes demonstrated that ΔCD98hc-β geo fusion protein preserved its ability to interact with integrin β1 although this mutant protein was hardly localized on the cell surface. These findings suggest that ΔCD98hc-β geo protein can mediate integrin signaling but cannot support amino acid transport through LATs. CD98hcΔ/+ mice were normal. Although some of the implantation sites lacked embryonic component at E9.5, all the implantation sites contained embryonic component at E7.5. Thus, CD98hcΔ/Δ embryos are likely to die between E7.5 and E9.5.ConclusionsConsidering that CD98hc complete knockout (CD98hc-/-) embryos are reported to die shortly after implantation, our findings suggest potential stage-specific roles of CD98hc in murine embryonic development. CD98hc may be essential for early post-implantation development by regulating integrin-dependent signaling, while the other function of CD98hc as a component of amino acid transporters may be required for embryonic development at later stages.
Highlights
The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin b1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of embryonic stem (ES) cell proliferation
CD98hc mRNA is expressed in multiple adult and fetal tissues Northern blot analysis revealed that CD98hc is expressed in a wide variety of adult tissues (Figure 1A)
These results suggest that CD98hc play roles in various organs and during embryogenesis
Summary
The multifunctional protein CD98 heavy chain (CD98hc, Slc3a2) associates with integrin b1 through its cytoplasmic and transmembrane domains and the CD98hc-mediated integrin signaling is required for maintenance of ES cell proliferation. The extracellular domain of CD98hc interacts with L-type amino acid transporters (LATs) and is essential for appropriate cell surface distribution of LATs. LATs mediate the transport of amino acids and other molecules such as thyroid hormone. CD98hc-/- ES cells rarely form teratocarcinoma in nude mice due to severely impaired proliferative activity. These lethal phenotypes of CD98hc-/- ES cells are completely rescued by concomitant overexpression of chimeric CD98hc protein whose extracellular domain is replaced by that of unrelated transmembrane protein [11], indicating that cytoplasmic and transmembrane domains of CD98hc that mediate integrin b1 interaction are sufficient to support ES cell proliferation. Lack of CD98hc-mediated integrin signaling is a likely cause of reduced proliferation in CD98hc-null ES cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
