The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway

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

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Main Authors:	Hennigan, Robert F., Moon, Chandra A., Parysek, Linda M., Monk, Kelly R., Morfini, Gerardo, Berth, Sarah, Brady, Scott, Ratner, Nancy
Format:	Online
Language:	English
Published:	2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260777/

id	pubmed-4260777
recordtype	oai_dc
spelling	pubmed-42607772014-12-09 The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway Hennigan, Robert F. Moon, Chandra A. Parysek, Linda M. Monk, Kelly R. Morfini, Gerardo Berth, Sarah Brady, Scott Ratner, Nancy Article Neurofibromatosis Type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adaptor 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 p38SAPK, 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 p38SAPK 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. 2012-04-23 2013-02-28 /pmc/articles/PMC4260777/ /pubmed/22525268 http://dx.doi.org/10.1038/onc.2012.135 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hennigan, Robert F. Moon, Chandra A. Parysek, Linda M. Monk, Kelly R. Morfini, Gerardo Berth, Sarah Brady, Scott Ratner, Nancy
spellingShingle	Hennigan, Robert F. Moon, Chandra A. Parysek, Linda M. Monk, Kelly R. Morfini, Gerardo Berth, Sarah Brady, Scott Ratner, Nancy The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
author_facet	Hennigan, Robert F. Moon, Chandra A. Parysek, Linda M. Monk, Kelly R. Morfini, Gerardo Berth, Sarah Brady, Scott Ratner, Nancy
author_sort	Hennigan, Robert F.
title	The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
title_short	The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
title_full	The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
title_fullStr	The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
title_full_unstemmed	The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway
title_sort	nf2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel rac, mlk and p38sapk pathway
description	Neurofibromatosis Type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adaptor 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 p38SAPK, 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 p38SAPK 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.
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260777/
_version_	1613165733517197312

The NF2 Tumor Suppressor Regulates Microtubule-Based Vesicle Trafficking via a Novel Rac, MLK and p38SAPK Pathway

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