Furthermore, previous studies suggested two distinct functions of CD98hc: ( i) It can associate with and regulate the function of selected integrins ( 5– 8), and ( ii) it can regulate the expression and distribution of the light chains to modulate amino acid transport function ( 3). Overexpression of CD98hc transforms NIH 3T3 cells ( 4). CD98hc is highly expressed on proliferating lymphocytes and on other rapidly growing cells ( 3). CD98 (4F2 antigen) is expressed on a family of heterodimers composed of a common type II transmembrane heavy chain (CD98hc, 4F2hc, SLC3A2) and one of several light chains ( 3). The β1 integrins regulate numerous cellular functions by signaling through a variety of biochemical pathways ( 1, 2). Thus, CD98hc is an integrin-associated protein that mediates integrin-dependent signals, which promote tumorigenesis. CD98hc deletion markedly impaired the ability of embryonic stem cells to form teratocarcinomas in mice teratocarcinoma formation was reconstituted by reexpression of CD98hc or of the mutant that interacts exclusively with integrins. β1 integrins are involved in the pathogenesis of certain cancers. CD98 promotes amino acid transport through its light chains however, a CD98hc mutant that interacts with β1 integrins, but not CD98 light chains, restored integrin-dependent signaling and protection from apoptosis. Furthermore, CD98hc is required for efficient adhesion-induced activation of Akt and Rac GTPase, major contributors to the integrin-dependent signals involved in cell survival and cell migration. Here we report that CD98hc contributes to integrin-dependent cell spreading, cell migration, and protection from apoptosis. To establish the biological function of CD98hc, we disrupted the gene and analyzed CD98hc-null cells. CD98hc overexpression leads to anchorage-independent cell growth and tumorigenesis in 3T3 fibroblasts and activates certain integrin-regulated signaling pathways.
CD98 heterodimers, comprised of a heavy chain (CD98hc, SLC3A2) and one of several light chains, interact with integrins through CD98hc. Integrins regulate cellular behaviors through signaling pathways, including Rho GTPases and kinases.
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