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PMID:17190838

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Citation

Liu, Y, Zhu, M, Nishida, K, Hirano, T and Zhang, W (2007) An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. J. Exp. Med. 204:93-103

Abstract

Cross-linking of the FcepsilonRI activates the phosphatidyl inositol 3 kinase (PI3K) and mitogen-activated protein kinase pathways. Previous studies demonstrate that Ras guanyl nucleotide-releasing protein (RasGRP)1 is essential in T cell receptor-mediated Ras-Erk activation. Here, we report that RasGRP1 plays an important role in FcepsilonRI-mediated PI3K activation and mast cell function. RasGRP1-deficient mice failed to mount anaphylactic allergic reactions. RasGRP1-/- mast cells had markedly reduced degranulation and cytokine production. Although FcepsilonRI-mediated Erk activation was normal, PI3K activation was diminished. Consequently, activation of Akt, PIP3-dependent kinase, and protein kinase C delta was defective. Expression of a constitutively active form of N-Ras could rescue the degranulation defect and Akt activation. We further demonstrated that RasGRP1-/- mast cells were defective in granule translocation, microtubule formation, and RhoA activation. Our results identified RasGRP1 as an essential regulator of mast cell function.

Links

PubMed PMC2118421 Online version:10.1084/jem.20061598

Keywords

Anaphylaxis/etiology; Anaphylaxis/immunology; Anaphylaxis/physiopathology; Animals; Cell Degranulation; Cytokines/biosynthesis; Enzyme Activation; Guanine Nucleotide Exchange Factors/deficiency; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/immunology; Guanine Nucleotide Exchange Factors/physiology; Immunoglobulin E/metabolism; MAP Kinase Signaling System; Mast Cells/immunology; Mast Cells/physiology; Mice; Mice, Knockout; Models, Biological; Phosphatidylinositol 3-Kinases/metabolism; Receptors, IgE/metabolism; Signal Transduction

Significance

Annotations

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

MOUSE:GRP1

acts_upstream_of_or_within

GO:0032252: secretory granule localization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

  • occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0014066: regulation of phosphatidylinositol 3-kinase signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

  • regulates_o_occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

  • regulates_o_occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0047496: vesicle transport along microtubule

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

  • occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0032252: secretory granule localization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0014066: regulation of phosphatidylinositol 3-kinase signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

regulates_o_occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0043303: mast cell degranulation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0090630: activation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

regulates_o_occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0047496: vesicle transport along microtubule

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

occurs_in:(CL:0000097)

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0001816: cytokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

Seeded From UniProt

complete

MOUSE:GRP1

acts_upstream_of_or_within

GO:0002437: inflammatory response to antigenic stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2386261

P

Seeded From UniProt

complete


See also

References

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