RabGEF1 is a negative regulator of mast cell activation and skin inflammation.
Mast cell activation induced by aggregation of Fc epsilon RI receptors with immunoglobulin E and antigen is mediated through the activation of multiple protein kinase cascades. Here we report that the regulatory protein RabGEF1 bound to Ras and negatively regulated Ras activation and its 'downstream' effector pathways in Fc epsilon RI-dependent mast cell activation. RabGEF1-deficient mast cells showed enhanced degranulation and release of lipid mediators and cytokines in response to Fc epsilon RI aggregation. RabGEF1-deficient mice developed severe skin inflammation and had increased numbers of mast cells. Thus, RabGEF1 is a negative regulator of Fc epsilon RI-dependent mast cell activation, and a lack of RabGEF1 results in the development of skin inflammation in vivo.
Tam
See-Ying
SY
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. stam@stanford.edu
Tsai
Mindy
M
Snouwaert
John N
JN
Kalesnikoff
Janet
J
Scherrer
Didier
D
Nakae
Susumu
S
Chatterjea
Devavani
D
Bouley
Donna M
DM
Galli
Stephen J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D005434:Flow Cytometry; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000276:immunology / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D017455:Receptors, IgE; D018631:ras Proteins