title: The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38(SAPK) pathway.
abstract: 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(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(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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Robert.Hennigan@cchmc.org
authors.forename: R F
authors.initials: RF
authors.lastname: Hennigan
authors.forename: C A
authors.initials: CA
authors.lastname: Moon
authors.forename: L M
authors.initials: LM
authors.lastname: Parysek
authors.forename: K R
authors.initials: KR
authors.lastname: Monk
authors.forename: G
authors.initials: G
authors.lastname: Morfini
authors.forename: S
authors.initials: S
authors.lastname: Berth
authors.forename: S
authors.initials: S
authors.lastname: Brady
authors.forename: N
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D002460:Cell Line; D049832:Decapodiformes; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D009442:Neurilemmoma / Q000378:metabolism; D025581:Neurofibromin 2 / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D025581:Neurofibromin 2; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C428384:MLK-like mitogen-activated protein triple kinase