Altered adhesive structures and their relation to RhoGTPase activation in merlin-deficient Schwannoma.
Schwannomas are Schwann cell tumors of the nervous system that occur spontaneously and in patients with neurofibromatosis 2 (NF2) and lack the tumor suppressor merlin. Merlin is known to bind paxillin, beta1 integrin and focal adhesion kinase, members of focal contacts, multi-protein complexes that mediate cell adhesion to the extracellular matrix. Moreover, merlin-deficient Schwannomas show pathological adhesion to the extracellular matrix making the characterization of focal contacts indispensable. Using our Schwannoma in vitro model of human primary Schwann and Schwannoma cells, we here show that Schwannoma cells display an increased number of mature and stable focal contacts. In addition to an involvement of RhoA signaling via the Rho kinase ROCK, Rac1 plays a significant role in the pathological adhesion of Schwannoma cells. The Rac1 guanine exchange factor- beta-Pix, localizes to focal contacts in human primary Schwannoma cells, and we show that part of the Rac1 activation, an effect of merlin-deficiency, occurs at the level of focal contacts in human primary Schwannoma cells. Our results help explaining the pathological adhesion of Schwannoma cells, further strengthen the importance of RhoGTPase signaling in Schwannoma development, and suggest that merlin's role in tumor suppression is linked to focal contacts.
Flaiz
Christine
C
Department of Clinical Neurobiology, Institute of Biomedical and Clinical Science, Peninsula College for Medicine and Dentistry, Plymouth, UK.
Ammoun
Sylwia
S
Biebl
Anja
A
Hanemann
C Oliver
CO
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000577:Amides / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000172:deficiency* / Q000235:genetics; D051419:Paxillin / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D064067:Rho Guanine Nucleotide Exchange Factors; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C576606:ARHGEF7 protein, human; D000199:Actins; D000577:Amides; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D025581:Neurofibromin 2; D051419:Paxillin; D010455:Peptides; D011725:Pyridines; D064067:Rho Guanine Nucleotide Exchange Factors; C487017:WR-PAK18 peptide; C108830:Y 27632; D049452:Green Fluorescent Proteins; D054460:rho-Associated Kinases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein