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PMID:17341663

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Citation

Kalesnikoff, J, Rios, EJ, Chen, CC, Alejandro Barbieri, M, Tsai, M, Tam, SY and Galli, SJ (2007) Roles of RabGEF1/Rabex-5 domains in regulating Fc epsilon RI surface expression and Fc epsilon RI-dependent responses in mast cells. Blood 109:5308-17

Abstract

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.

Links

PubMed PMC1890836 Online version:10.1182/blood-2007-01-067363

Keywords

Bone Marrow Cells; Cell Degranulation; Cells, Cultured; Endocytosis; Gene Expression Regulation; Guanine Nucleotide Exchange Factors/chemistry; Guanine Nucleotide Exchange Factors/physiology; Humans; Interleukin-6/biosynthesis; Mast Cells/cytology; Mast Cells/physiology; Receptors, IgE/deficiency; Receptors, IgE/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RABE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q9JM13

F

Seeded From UniProt

complete

MOUSE:RABX5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O35551

F

Seeded From UniProt

complete

MOUSE:RABX5

located_in

GO:0031982: vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000097)
  • part_of:(EMAPA:32760)

Seeded From UniProt

complete

MOUSE:RABX5

acts_upstream_of_or_within

GO:0060368: regulation of Fc receptor mediated stimulatory signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000097)
  • regulates_o_occurs_in:(EMAPA:32760)

Seeded From UniProt

complete

MOUSE:RABX5

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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