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Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44
Monika Hartmann1, Liseth M Parra2, Anne Ruschel1
1Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
Unlabelled:
Ectodomain cleavage (shedding) of transmembrane proteins by metalloproteases (MMP) generates numerous essential signaling molecules, but its regulation is not totally understood. CD44, a cleaved transmembrane glycoprotein, exerts both antiproliferative or tumor-promoting functions, but whether proteolysis is required for this is not certain. CD44-mediated contact inhibition and cellular proliferation are regulated by counteracting CD44 C-terminal interacting proteins, the tumor suppressor protein merlin (NF2) and ERM proteins (ezrin, radixin, moesin). We show here that activation or overexpression of constitutively active merlin or downregulation of ERMs inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced [as well as serum, hepatocyte growth factor (HGF), or platelet-derived growth factor (PDGF)] CD44 cleavage by the metalloprotease ADAM10, whereas overexpressed ERM proteins promoted cleavage. Merlin- and ERM-modulated Ras or Rac activity was not required for this function. However, latrunculin (an actin-disrupting toxin) or an ezrin mutant which is unable to link CD44 to actin, inhibited CD44 cleavage, identifying a cytoskeletal C-terminal link as essential for induced CD44 cleavage. Cellular migration, an important tumor property, depended on CD44 and its cleavage and was inhibited by merlin. These data reveal a novel function of merlin and suggest that CD44 cleavage products play a tumor-promoting role. Neuregulin, an EGF ligand released by ADAM17 from its pro-form NRG1, is predominantly involved in regulating cellular differentiation. In contrast to CD44, release of neuregulin from its pro-form was not regulated by merlin or ERM proteins. Disruption of the actin cytoskeleton however, also inhibited NRG1 cleavage. This current study presents one of the first examples of substrate-selective cleavage regulation.
Implications:
Investigating transmembrane protein cleavage and their regulatory pathways have provided new molecular insight into their important role in cancer formation and possible treatment.
Insights
The tumor suppressor merlin (NF2) regulates CD44 ectodomain shedding by metalloproteases (MMP), impacting cellular migration and suggesting a tumor-promoting role for CD44 cleavage products.
Area of Science:
- Molecular and Cellular Biology
- Cancer Research
- Protease Signaling
Background:
- Ectodomain cleavage of transmembrane proteins by metalloproteases (MMP) generates signaling molecules, but regulation is poorly understood.
- CD44 shedding influences cell proliferation and tumor promotion, with its regulation by merlin (NF2) and ERM proteins unclear.
- Actin cytoskeleton linkage is implicated in regulating protein cleavage.
Purpose of the Study:
- To investigate the role of merlin and ERM proteins in regulating CD44 ectodomain cleavage.
- To determine the involvement of the actin cytoskeleton in CD44 cleavage.
- To explore the impact of CD44 cleavage on cellular migration and its potential role in cancer.
Main Methods:
- Manipulation of merlin and ERM protein expression levels.
- Induction of CD44 cleavage using various growth factors and phorbol esters.
- Assessment of CD44 cleavage using biochemical assays and analysis of cellular migration.
Main Results:
- Merlin activation or ERM downregulation inhibited TPA-induced CD44 cleavage, while ERM overexpression promoted it.
- CD44 cleavage was dependent on cytoskeletal linkage, as shown by inhibition with latrunculin or an ezrin mutant.
- Merlin inhibited CD44-dependent cellular migration, suggesting CD44 cleavage products have tumor-promoting functions.
Conclusions:
- Merlin and ERM proteins differentially regulate CD44 ectodomain cleavage.
- Actin cytoskeleton linkage is essential for induced CD44 cleavage.
- CD44 cleavage products may play a tumor-promoting role, offering potential therapeutic targets.
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