The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44

Abstract

The neurofibromatosis-2 (NF2) gene encodes merlin, an ezrin-radixin-moesin-(ERM)-related protein that functions as a tumor suppressor. We found that merlin mediates contact inhibition of growth through signals from the extracellular matrix. At high cell density, merlin becomes hypo-phosphorylated and inhibits cell growth in response to hyaluronate (HA), a mucopolysaccharide that surrounds cells. Merlin's growth-inhibitory activity depends on specific interaction with the cytoplasmic tail of CD44, a transmembrane HA receptor. At low cell density, merlin is phosphorylated, growth permissive, and exists in a complex with ezrin, moesin, and CD44. These data indicate that merlin and CD44 form a molecular switch that specifies cell growth arrest or proliferation.

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

“…Ezrin, another member of the ERM family, is reported to participate in Src signaling and to induce FAK activation (Poullet et al, 2001;Srivastava et al, 2005) Although ezrin and merlin have similarities in structure and common interacting partners, such as CD44, NHERF and N-WASP (Bretscher et al, 2000;Morrison et al, 2001;Martin et al, 2003;Manchanda et al, 2005), they possess opposite functions in cell growth and proliferation. As we observed an inhibitory effect of merlin on cell migration and invasion, we sought to determine if merlin could downregulate FAK.…”

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

“…Tr6BC1 cells were stably transfected with cDNAs encoding wt merlin or one of the five deletion mutants of merlin and at least three independent colonies expressing an intermediate to high level of each of these cDNAs were identified ( Figure 2B-a). The double banding pattern observed by Western blotting analysis is characteristic of merlin and represents phosphorylated and un-phosphorylated forms of the protein (Morrison et al, 2001). The slight difference in molecular weight of the merlin deletions reflects the differences in molecular weight of the deleted amino acids.…”

“…CD44, the principal cell-surface receptor for hyaluronan (HA; Stamenkovic et al, 1989;Aruffo et al, 1990), is one of the transmembrane proteins that interact with ERM proteins and merlin (Tsukita et al, 1994;Hirao et al, 1996;Sainio et al, 1997;Tsukita and Yonemura, 1997;Morrison et al, 2001). There are numerous isoforms of CD44, the most commonly expressed isoform is the standard form of CD44 (CD44s) that lacks variant exon products.…”

“…Merlin has been shown to mediate the contact inhibition of cell growth in vitro via its interaction with CD44 (Morrison et al, 2001) and loss of merlin promotes tumorigenesis by destabilizing the cadherin-mediated adherens junctions (Lallemand et al, 2003). However, neither the mechanism whereby merlin exerts its tumor-suppressing activity nor the precise functional relationship between merlin and CD44 has been fully elucidated.…”

CD44, un régulateur de la croissance et de l’invasion cellulaire

“…L'une des molécules appartenant à cette famille, la merline -produit du gène NF2 -est un suppresseur de tumeur [14]. Dans les conditions de culture où les cellules s'arrêtent de proliférer, la merline est active, déphosphorylée; elle se lie à CD44 et interfère avec les signaux de transduction, ce qui aboutit finalement à l'arrêt de la croissance cellulaire [15]. Les situations pathologiques dans lesquelles la fonction de CD44 en tant que corécepteur de c-Met dominent donneraient lieu à une prolifération non contrôlée des cellules aboutissant au développement de tumeurs.…”