RabGEF1 is a negative regulator of mast cell activation and skin inflammation

Abstract

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.

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

“…of Rabex-5 in mast cells, suggesting that the phenotype of Rabex-5-deficient mice might reflect, at least in part, defective mast cell function (4,25,26). Here, we have reported that Rabex-5 is a critical negative regulator of type 1 IFN production.…”

“…Here, we identify Rabex-5 as an IMiD target molecule. The phenotype of Rabex-5-deficient mice, which spontaneously develop a fatal inflammatory skin disorder (4), taken together with our observations here, strongly suggests the involvement of Rabex-5 in mediating IMiD properties.…”

“…Mechanistically, Rabex-5 is reported to regulate immune responses via the negative regulation of RasGTPase activated pathways (4,25,26). Previous studies have focused on the function D).…”

“…Studies of Rabex-5 function in immunity have shown the Ras family of GTPases to be an important target of Rabex-5 function. Ras is constitutitvely active in Rabex-5-deficient mast cells generated in vitro, resulting in enhanced production of IL6 in response to IgE and antigen stimulation in vitro (4). Therefore, Rabex-5 maintains immune homeostasis by preventing excessive Rasinduced immune responses.…”

Rabaptin-5-independent Membrane Targeting and Rab5 Activation by Rabex-5 in the Cell

“…A coiled-coil domain downstream of the GEF domain may mediate the binding to Rabaptin-5, as shown in a yeast two-hybrid assay , whereas a Zn 2ϩ finger (ZnF) domain at the N terminus is shown to bind ubiquitin (Lee et al, 2006;Mattera et al, 2006;Penengo et al, 2006). Recently, Rabex-5 (also called Rab-GEF1) knockout mice have been generated, and they die early and develop severe skin inflammation (Tam et al, 2004). Mast cells isolated from these Rabex-5-deficient mice show enhanced stem cell factor/c-Kit-mediated signal transduction and biological responses (Kalesnikoff et al, 2006).…”