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

R. F. Hennigan, C. A. Moon, L. M. Parysek, Kelly Monk, G. Morfini, S. Berth, S. Brady, N. Ratner

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1135-1143
Number of pages9
JournalOncogene
Volume32
Issue number9
DOIs
StatePublished - Feb 28 2013
Externally publishedYes

Fingerprint

Neurofibromin 2
p38 Mitogen-Activated Protein Kinases
Microtubules
Neoplasms
Growth Factor Receptors
Schwann Cells
Neurilemmoma
Phosphotransferases
Neurofibromatosis 2
Contact Inhibition
Ependymoma
Transport Vesicles
Decapodiformes
Mutation
GTP Phosphohydrolases
Meningioma
Tumor Suppressor Genes
Cytoskeleton
Membranes

Keywords

  • exocytosis
  • merlin
  • NF2
  • Rac
  • trafficking

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Hennigan, R. F., Moon, C. A., Parysek, L. M., Monk, K., Morfini, G., Berth, S., ... Ratner, N. (2013). The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38 SAPK pathway. Oncogene, 32(9), 1135-1143. https://doi.org/10.1038/onc.2012.135

The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38 SAPK pathway. / Hennigan, R. F.; Moon, C. A.; Parysek, L. M.; Monk, Kelly; Morfini, G.; Berth, S.; Brady, S.; Ratner, N.

In: Oncogene, Vol. 32, No. 9, 28.02.2013, p. 1135-1143.

Research output: Contribution to journalArticle

Hennigan, RF, Moon, CA, Parysek, LM, Monk, K, Morfini, G, Berth, S, Brady, S & Ratner, N 2013, 'The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38 SAPK pathway', Oncogene, vol. 32, no. 9, pp. 1135-1143. https://doi.org/10.1038/onc.2012.135
Hennigan, R. F. ; Moon, C. A. ; Parysek, L. M. ; Monk, Kelly ; Morfini, G. ; Berth, S. ; Brady, S. ; Ratner, N. / The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38 SAPK pathway. In: Oncogene. 2013 ; Vol. 32, No. 9. pp. 1135-1143.
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