The tumor suppressor merlin interacts with microtubules and modulates Schwann cell microtubule cytoskeleton.
The lack of neurofibromatosis 2 tumor suppressor protein merlin leads to the formation of nervous system tumors, specifically schwannomas and meningiomas. Merlin is considered to act as a tumor suppressor at the cell membrane, where it links transmembrane receptors to the actin cytoskeleton. Several tumor suppressors interact with another component of the cytoskeleton, the microtubules, in a regulated manner and control their dynamics. In this work, we identify merlin as a novel microtubule-organizing protein. We identify two tubulin-binding sites in merlin, one residing at the N-terminal FERM-domain and another at the C-terminal domain. Merlin's intramolecular association and phosphorylation of serine 518 regulate the interaction between merlin and tubulin. Analysis of cultured glioma cells indicates colocalization between merlin and microtubules especially during cell division. In primary mouse Schwann cells only minor colocalization at the cell periphery of interphase cells is seen. However, these cells drastically change their microtubule organization upon loss of merlin indicating a functional association of the proteins. Both in vitro assays and in vivo studies in Schwann cells indicate that merlin promotes tubulin polymerization. The results show that merlin plays a key role in the regulation of the Schwann cell microtubule cytoskeleton and suggest a mechanism by which loss of merlin leads to cytoskeletal defects observed in human schwannomas.
Muranen
Taru
T
Program of Neuroscience, Department of Pathology, University of Helsinki, Biomedicum Helsinki C511, PL 63, 0014, Finland. taru.muranen@helsinki.fi
Grönholm
Mikaela
M
Lampin
Aurelie
A
Lallemand
Dominique
D
Zhao
Fang
F
Giovannini
Marco
M
Carpén
Olli
O
D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007313:Insecta; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms; D012583:Schwann Cells / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D025581:Neurofibromin 2; D020033:Protein Isoforms; D014404:Tubulin