Article

CD98hc (SLC3A2) interaction with beta(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

ABSTRACT 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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    • "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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