The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38 super(SAPK) pathway

Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor...

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Published inOncogene Vol. 32; no. 9; pp. 1135 - 1143
Main Authors Hennigan, R F, Moon, C A, Parysek, L M, Monk, K R, Morfini, G, Berth, S, Brady, S, Ratner, N
Format Journal Article
LanguageEnglish
Published 28.02.2013
Subjects
adaptor proteins
Cell migration
Cell surface
Contact inhibition
Data processing
Growth factor receptors
Guanosinetriphosphatase
meningioma
Motility
Mutation
Neurofibromatosis 2
Neurofibromin 2
Schwann cells
Tumor suppressor genes
Vesicles
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Summary:Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface. We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts. We found that schwannoma cells, containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases, had decreased intracellular vesicular trafficking relative to normal human Schwann cells. In Nf2-/- mouse Schwann (SC4) cells, re-expression of merlin as well as inhibition of Rac or its effector kinases, MLK and p38 super(SAPK), each increased the velocity of Rab6 positive exocytic vesicles. Conversely, an activated Rac mutant decreased Rab6 vesicle velocity. Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38 super(SAPK) kinase. Taken together, our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles, representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface.
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ISSN:0950-9232
DOI:10.1038/onc.2012.135