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Roles of RabGEF1/Rabex-5 domains in regulating Fc epsilon RI surface expression and Fc epsilon RI-dependent responses in mast cells.

RabGEF1/Rabex-5, a guanine nucleotide exchange factor (GEF) for the endocytic pathway regulator, Rab5, contains a Vps9 domain, an A20-like zinc finger (ZnF) domain, and a coiled coil domain. To investigate the importance of these domains in regulating receptor internalization and cell activation, we lentivirally delivered RabGEF1 mutants into RabGEF1-deficient (-/-) mast cells and examined Fc epsilon RI-dependent responses. Wild-type RabGEF1 expression corrected phenotypic abnormalities in -/- mast cells, including decreased basal Fc epsilon RI expression, slowed Fc epsilon RI internalization, elevated IgE + Ag-induced degranulation and IL-6 production, and the decreased ability of -/- cytosol to support endosome fusion. We showed that RabGEF1's ZnF domain has ubiquitin ligase activity. Moreover, the coiled coil domain of RabGEF1 is required for Rabaptin-5 binding and for maintaining basal levels of Rabaptin-5 and surface Fc epsilon RI. However, mutants lacking either of these domains normalized phenotypic abnormalities in IgE + antigen-activated -/- mast cells. By contrast, correction of these -/- phenotypes required a functional Vps9 domain. Thus, Fc epsilon RI-mediated mast cell functional activation is dependent on RabGEF1's GEF activity.

Pubmed ID: 17341663

Authors

  • Kalesnikoff J
  • Rios EJ
  • Chen CC
  • Alejandro Barbieri M
  • Tsai M
  • Tam SY
  • Galli SJ

Journal

Blood

Publication Data

June 15, 2007

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI070813
  • Agency: NIAID NIH HHS, Id: AI23990
  • Agency: NCI NIH HHS, Id: CA72074
  • Agency: NIGMS NIH HHS, Id: GM08205
  • Agency: NHLBI NIH HHS, Id: HL67674

Mesh Terms

  • Bone Marrow Cells
  • Cell Degranulation
  • Cells, Cultured
  • Endocytosis
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Interleukin-6
  • Mast Cells
  • Receptors, IgE