RabGEF1, also known as Rabex-5, is a guanine nucleotide exchange factor for RAB-5. It plays a crucial role in regulating early endosome fusion and vesicular trafficking in endocytic pathways, which are essential for multiple cellular functions like membrane turnover, signal transduction, protein recycling, and degradation [3,5]. It is involved in various signaling pathways such as p38 MAPK-dependent pathway, AKT and Erk pathways, and is associated with biological processes including cell proliferation, differentiation, and inflammation [1,2]. Genetic models, especially KO/CKO mouse models, have been valuable in studying its functions.

In mouse models, IEC-specific Rabgef1 deletion led to a delayed spontaneous colitis and exacerbated intestinal pathology in colitis models, suggesting its role in maintaining intestinal homeostasis by regulating IEC-intrinsic MYD88-dependent innate signaling [1]. In glioblastoma cells, knockdown of RabGEF1 inhibited cell proliferation, metastasis, and induced autophagy, potentially mediated by inactivation of AKT and Erk signaling pathways [2]. In NGF-differentiated PC12 cells, RabGEF1 negatively regulated NGF-induced neurite outgrowth and NMDA-induced signaling activation [3]. Also, in mast cells, RabGEF1-deficient mice showed enhanced mast cell activation and skin inflammation, with RabGEF1 negatively regulating Ras activation in FcεRI-dependent mast cell activation [4]. In keratinocytes, keratinocyte-specific deletion of RabGEF1 impaired epidermal barrier function, induced an allergic phenotype, and was associated with aberrant activation of the IL-1R/MYD88/NF-κB signaling pathway [6].

In conclusion, RabGEF1 plays diverse and significant roles in multiple biological processes and disease conditions. KO/CKO mouse models have been instrumental in revealing its functions in intestinal inflammation, glioblastoma, neuronal differentiation, mast cell-mediated skin inflammation, and skin homeostasis. These findings suggest that RabGEF1-dependent pathways could be potential therapeutic targets for diseases related to these areas.