CD98hc (SLC3A2) Interaction with 1 Integrins Is Required for Transformation

Vanderbilt University, Нашвилл, Michigan, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2005; 279(52):54731-41. DOI: 10.1074/jbc.M408700200
Source: PubMed


CD98hc (SLC3A2) constitutively and specifically associates with beta(1) integrins and is highly expressed on the surface of human tumor cells irrespective of the tissue of origin. We have found here that expression of CD98hc promotes both anchorage- and serum-independent growth. This oncogenic activity is dependent on beta(1) integrin-mediated phosphoinositol 3-hydroxykinase stimulation and the level of surface expression of CD98hc. Using chimeras of CD98hc and the type II membrane protein CD69, we show that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/beta(1) integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumor promotion by integrins. These results explain how high expression of CD98hc in human cancers contributes to transformation; furthermore, the transmembrane association of CD98hc and beta(1) integrins may provide a new target for cancer therapy.

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    • "In addition to its important role in the adaptive immunity, CD98 have been shown to be expressed by solid tumors where it promotes transformation, tumor growth and progression [18], [24], [25]. Center and Ginsberg conclude that the benefits of the adaptive immunity come with a price, in this case increased susceptibility to invasive cancer [18]. "
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    ABSTRACT: Several epidemiological studies have investigated the relation between allergy and cancer with contradicting conclusions, and reports on immunological differences are scarce. By focusing on inflammation, the present study was designed to compare the immune response induced by allergic rhinitis (AR) and head and neck squamous cell carcinoma (HNSCC). Blood and serum was obtained from patients with symptomatic seasonal AR, and newly detected HNSCC, as well as healthy controls. Peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) were isolated and cultured with or without the toll-like receptor ligands, Pam3CSK4, LPS, R837, and CpG. Cellular activation and cytokine release were assessed with ELISA, Luminex Multiplex Immunoassay, flow cytometry, and real-time RT-PCR. Sera from HNSCC patients showed elevated levels of innate immune cytokines, and exhibited a response profile consistent with an increased innate immune reaction. In contrast, sera and stimulated PBMC from AR patients displayed increased concentrations of T cell related cytokines, consistent with an adaptive immune response. The presented data demonstrate that AR and HNSCC induce two distinct immunological processes, indicating an inverse association between the immunological responses seen in patients with allergy and cancer of the upper airway.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "One could speculate that the interaction partners for CD98hc beta 1 integrins as well as beta 3 integrins, which are both expressed in CaKi2 cells and have previously been shown to interact with CD98hc [9,10], were mediating adhesion-induced signal transduction via induction of FAK and c-src whenever CD98hc was present. This is also supported by the fact that whenever the cytoplasmic domain of CD98hc for integrin binding was absent, for instance in CD98hc reconstituted cells, a diminished FAK phosphorylation upon cell adhesion on a beta 1 integrin as well as beta 3 integrin-specific matrix protein was observed. "
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    ABSTRACT: Overexpression of CD98hc (SLC3A2) occurs in a variety of cancers and is suspected to contribute to tumor growth. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin beta subunit cytoplasmic domains via its heavy chain, CD98hc. CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thereby, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E 3.5 and E 9.5) and CD98hc -/- embryonic stem cell transplantation failed to form teratomas, while CD98hc over-expression in somatic cells resulted in anchorage-independent growth. However, it is unclear whether interference with CD98hc expression affects tumorigenesis. Renal cell cancer cell lines have been used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometric analysis was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to stably knockdown or reconstitute full length or mutated CD98hc. The role of CD98 as a promotor of tumorigenesis was evaluated using an in in vivo tumor transplantation animal model. Immunohistochemical analysis was performed to analyze cell proliferation and CD98 expression in tumors. This report shows that CD98hc silencing in clear cell renal cancer cells reverts certain characteristics of tumorigenesis, including cell spreading, migration, proliferation and survival in vitro, and tumor growth in vivo. Acquisition of tumorigenic characteristics in clear cell renal cancer cells occurred through the integrin binding domain of CD98hc. A CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued the CD98hc deficiency. In this study we demonstrate that loss of CD98hc blocks tumorigenic potential in renal cell cancer.
    Full-text · Article · Dec 2013 · Molecular Cancer
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    • "Adhesion of control and Fam38A-siRNA cells, were assessed by standard methods as described in [22]. Colony assays were performed as described in [23], 72 hours post-siRNA treatment, using 5×105 treated live cells. Colonies were counted by phase microscopy after staining with nitro blue tetrazoleum solution. "
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