title: Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44.
abstract: 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.
  
  
  CONCLUSIONS
  Investigating transmembrane protein cleavage and their regulatory pathways have provided new molecular insight into their important role in cancer formation and possible treatment.
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Monika
authors: M
authors: Hartmann
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany. Harvard Institutes of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Liseth M
authors: LM
authors: Parra
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Anne
authors: A
authors: Ruschel
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Sandra
authors: S
authors: Böhme
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Yong
authors: Y
authors: Li
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Helen
authors: H
authors: Morrison
authors: Harvard Institutes of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. herrlich@fli-leibniz.de aherrlich@partners.org.
authors: Andreas
authors: A
authors: Herrlich
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany. herrlich@fli-leibniz.de aherrlich@partners.org.
authors: Peter
authors: P
authors: Herrlich
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D025581:Neurofibromin 2