Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for NF1+/- mast cells

Feng Chun Yang, David A. Ingram, Shi Chen, Cynthia M. Hingtgen, Nancy Ratner, Kelly R. Monk, Travis Clegg, Hilary White, Laura Mead, Mary Jo Wenning, David A. Williams, Reuben Kapur, Simon J. Atkinson, D. Wade Clapp

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153 Scopus citations

Abstract

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.

Original languageEnglish (US)
Pages (from-to)1851-1861
Number of pages11
JournalJournal of Clinical Investigation
Volume112
Issue number12
DOIs
StatePublished - Dec 1 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Yang, F. C., Ingram, D. A., Chen, S., Hingtgen, C. M., Ratner, N., Monk, K. R., Clegg, T., White, H., Mead, L., Wenning, M. J., Williams, D. A., Kapur, R., Atkinson, S. J., & Clapp, D. W. (2003). Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for NF1+/- mast cells. Journal of Clinical Investigation, 112(12), 1851-1861. https://doi.org/10.1172/JCI200319195