Hyperactivation of p21ras and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro

David Ingram, Kelly Hiatt, Alastair J. King, Lucy Fisher, Rama Shivakumar, Christina Derstine, Mary Jo Wenning, Bruce Diaz, Jeffrey Travers, Antoinette Hood, Mark Marshall, David A. Williams, D. Clapp

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/- and Rac2-/- mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal-regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/- mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.

Original languageEnglish
Pages (from-to)57-69
Number of pages13
JournalJournal of Experimental Medicine
Volume194
Issue number1
DOIs
StatePublished - Jul 2 2001

Fingerprint

Neurofibromin 1
rho GTP-Binding Proteins
Mast Cells
1-Phosphatidylinositol 4-Kinase
Extracellular Signal-Regulated MAP Kinases
Animal Disease Models
Neurofibroma
Inborn Genetic Diseases
Neurofibromatosis 1
Monomeric GTP-Binding Proteins
Cell Lineage
Guanosine Triphosphate
Tumor Suppressor Genes
Phenotype
Cell Line
Skin
Mutation
In Vitro Techniques

Keywords

  • Cross-talk
  • Neurofibromatosis type 1
  • P13-K
  • Pak
  • Rac

ASJC Scopus subject areas

  • Immunology

Cite this

Hyperactivation of p21ras and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. / Ingram, David; Hiatt, Kelly; King, Alastair J.; Fisher, Lucy; Shivakumar, Rama; Derstine, Christina; Wenning, Mary Jo; Diaz, Bruce; Travers, Jeffrey; Hood, Antoinette; Marshall, Mark; Williams, David A.; Clapp, D.

In: Journal of Experimental Medicine, Vol. 194, No. 1, 02.07.2001, p. 57-69.

Research output: Contribution to journalArticle

Ingram, David ; Hiatt, Kelly ; King, Alastair J. ; Fisher, Lucy ; Shivakumar, Rama ; Derstine, Christina ; Wenning, Mary Jo ; Diaz, Bruce ; Travers, Jeffrey ; Hood, Antoinette ; Marshall, Mark ; Williams, David A. ; Clapp, D. / Hyperactivation of p21ras and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. In: Journal of Experimental Medicine. 2001 ; Vol. 194, No. 1. pp. 57-69.
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abstract = "Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/- and Rac2-/- mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal-regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/- mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.",
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AU - Wenning, Mary Jo

AU - Diaz, Bruce

AU - Travers, Jeffrey

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