Isolation and Characterization of Schwann Cells from Neurofibromatosis Type 2 Patients

Rosenbaum, Claudia; Kluwe, Lan; Mautner, Victor‐F.; Friedrich, Reinhard E; Müller, Hans; Hanemann, C. Oliver

doi:10.1006/nbdi.1998.0179

Cited by 62 publications

(68 citation statements)

References 32 publications

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“…This data supports a model in which under growth inhibitory conditions (such as confluency) merlin is active, hypophosphorylated, and bound to CD44, where it may participate in downregulating signaling pathways that lead to cellular proliferation. In addition, cultured, patient-derived NF2-deficient Schwann cells exhibit many phenotypes identical to those seen in 3T3-Nf2 BBA cells, including lack of contact inhibition, anchorage-independent growth and increased cell proliferation (Rosenbaum et al, 1998). Taken together with our results, these data suggest that mutation of Nf2 leads to misregulation of pathways that direct proper responses to growth inhibitory signals, such as cell-cell contact.…”

Section: Discussionsupporting

confidence: 79%

Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

et al. 2002

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Section: Discussionsupporting

confidence: 79%

Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

et al. 2002

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“…Here we show that also merlin binds microtubules, regulates their polymerization and has an important role in the establishment of normal Schwann cell morphology. Schwannoma cells from patients display altered morphology with long, multiple extensions (34). According to our study this altered morphology seems to be associated with disturbed microtubule cytoskeleton, linking the interplay of merlin and tubulin to normal Schwann cell development and possibly to schwannoma formation.…”

Section: Discussionsupporting

confidence: 52%

Novel Molecular Interactions and Biological Functions of the Neurofibromatosis 2 Tumor Suppressor Protein, Merlin

Carpén¹

2008

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-08-2006 REPORT TYPE Annual DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of Helsinki Helsinki 00014 Finland SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe project studies molecular functions of neurofibromatosis 2 tumor suppressor protein merlin and compares the role of phosphorylation in regulation of merlin and structurally related ezrin. The role of different importin subunits in nuclear targeting of merlin was tested. Merlin bound several importin subunits in a non-selective manner. Merlin was shown to bind tubulin via two different regions, one located in the FERM-domain and one at the C-terminus. Intramolecular association and phosphorylation of S518 residue regulated tubulin binding. Merlin promoted microtubule polymerization in vitro and in vivo. Loss of merlin caused marked changes in microtubule organization and dynamics. Studies on merlin and HEI10, a cell cycle regulator, clarified the interaction mechanism and showed a role for merlin in regulation of the integrity of HEI10. Phosphorylation studies identified a second protein kinase A binding site in merlin. Finally, studies assessing the role of Src-induced tyrosine phosphorylation of ezrin were initiated. SUBJECT TERMS IntroductionThe neurofibromatosis 2 (NF2) gene product merlin and the ezrin-radixin-moesin (ERM) family protein ezrin are structurally related proteins that demonstrate some functional similarities and interact with each other, but possess opposite effects on cell growth. The experiments of this proposal aim to explore the poorly understood molecular and cell biological basis of the tumor suppressor function of merlin. Specific emphasis has been given to cell cycle stage-dependent targeting of merlin (task 1), analysis of molecular interactions of me...

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“…Laminins might regulate SC morphology through Schwannomin. The lack of Schwannomin in Schwannoma cells alters the characteristic bipolar shape of SCs, so that they are rounded in shape (Pelton et al, 1998;Rosenbaum et al, 1998). This phenotype is similar to SCs lacking laminins (Fig.…”

Section: Discussionmentioning

confidence: 82%

Laminin is required for Schwann cell morphogenesis

Chen

North

et al. 2009

Journal of Cell Science

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Development of the peripheral nervous system requires radial axonal sorting by Schwann cells (SCs). To accomplish sorting, SCs must both proliferate and undergo morphogenetic changes such as process extension. Signaling studies reveal pathways that control either proliferation or morphogenesis, and laminin is essential for SC proliferation. However, it is not clear whether laminin is also required for SC morphogenesis. By using a novel time-lapse live-cell-imaging technique, we demonstrated that laminins are required for SCs to form a bipolar shape as well as for process extension. These morphological deficits are accompanied by alterations in signaling pathways. Phosphorylation of Schwannomin at serine 518 and activation of Rho GTPase Cdc42 and Rac1 were all significantly decreased in SCs lacking laminins. Inhibiting Rac1 and/or Cdc42 activities in cultured SCs attenuated laminin-induced myelination, whereas forced activation of Rac1 and/or Cdc42 in vivo improved sorting and hypomyelinating phenotypes in SCs lacking laminins. These findings indicate that laminins play a pivotal role in regulating SC cytoskeletal signaling. Coupled with previous results demonstrating that laminin is critical for SC proliferation, this work identifies laminin signaling as a central regulator coordinating the processes of proliferation and morphogenesis in radial axonal sorting.

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Isolation and Characterization of Schwann Cells from Neurofibromatosis Type 2 Patients

Cited by 62 publications

References 32 publications

Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene

Novel Molecular Interactions and Biological Functions of the Neurofibromatosis 2 Tumor Suppressor Protein, Merlin

Laminin is required for Schwann cell morphogenesis

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