RabGEF1, also known as Rabex-5, is a guanine nucleotide exchange factor for RAB-5. It is involved in regulating early endosome fusion and vesicular trafficking in endocytic pathways, and plays a role in multiple biological processes and signaling pathways [3,7]. It is important for maintaining homeostasis in various tissues and its dysregulation is associated with disease development.

In gene knockout models, IEC-specific Rabgef1 deletion in mice led to a delayed spontaneous colitis, exacerbated intestinal pathology in colitis models, and dysregulated IEC innate pathways [1]. In U251 glioblastoma cells, down-regulation of RabGEF1 inhibited cell proliferation, metastasis, and induced autophagy [2]. In NGF-differentiated PC12 cells, RabGEF1 knockdown enhanced NGF-induced neurite outgrowth and Rac1 activation [3]. In L929 cells, RABGEF1 promoted TNF-induced necroptosis [4]. In non-small cell lung cancer, RABGEF1 was involved in KRAS degradation [5]. In mast cells, RabGEF1-deficient cells showed enhanced activation, and Rabgef1-deficient mice developed severe skin inflammation [6]. In photoreceptors, loss of Rabgef1 caused aberrant morphogenesis, altered autophagy, and retinal degeneration [7]. In keratinocytes, keratinocyte-specific deletion of RabGEF1 impaired epidermal barrier function and induced an allergic phenotype [8].

In conclusion, RabGEF1 is a key regulator in multiple biological processes. Mouse knockout models have revealed its roles in intestinal inflammation, glioblastoma, neuronal differentiation, necroptosis, lung cancer, mast cell activation, skin inflammation, photoreceptor function, and epidermal barrier function. Understanding RabGEF1's function provides potential therapeutic targets for related diseases.

References:

1. El Abbas, Sophie, Radermecker, Coraline, Bai, Qiang, Galli, Stephen J, Marichal, Thomas. 2019. Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling. In Mucosal immunology, 13, 96-109. doi:10.1038/s41385-019-0211-z. https://pubmed.ncbi.nlm.nih.gov/31628426/

2. Fan, Haitao, Xin, Tao, Dong, Xushuai, Guo, Hua, Pang, Qi. 2020. RabGEF1 functions as an oncogene in U251 glioblastoma cells and is involved in regulating AKT and Erk pathways. In Experimental and molecular pathology, 118, 104571. doi:10.1016/j.yexmp.2020.104571. https://pubmed.ncbi.nlm.nih.gov/33166495/

3. Tam, See-Ying, Lilla, Jennifer N, Chen, Ching-Cheng, Kalesnikoff, Janet, Tsai, Mindy. 2015. RabGEF1/Rabex-5 Regulates TrkA-Mediated Neurite Outgrowth and NMDA-Induced Signaling Activation in NGF-Differentiated PC12 Cells. In PloS one, 10, e0142935. doi:10.1371/journal.pone.0142935. https://pubmed.ncbi.nlm.nih.gov/26588713/

4. Chen, Danni, Chen, Yushi, Feng, Jianting, Li, Lisheng, Lin, Yingying. 2024. Guanine nucleotide exchange factor RABGEF1 facilitates TNF-induced necroptosis by targeting cIAP1. In Biochemical and biophysical research communications, 703, 149669. doi:10.1016/j.bbrc.2024.149669. https://pubmed.ncbi.nlm.nih.gov/38377943/

5. Chiang, Cheng-Yao, Fan, Songqing, Zheng, Hongmei, Xiao, Tian, Zheng, Duo. 2023. Methylation of KRAS by SETD7 promotes KRAS degradation in non-small cell lung cancer. In Cell reports, 42, 113003. doi:10.1016/j.celrep.2023.113003. https://pubmed.ncbi.nlm.nih.gov/37682707/

6. Tam, See-Ying, Tsai, Mindy, Snouwaert, John N, Bouley, Donna M, Galli, Stephen J. 2004. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. In Nature immunology, 5, 844-52. doi:. https://pubmed.ncbi.nlm.nih.gov/15235600/

7. Hargrove-Grimes, Passley, Mondal, Anupam K, Gumerson, Jessica, Li, Tiansen, Swaroop, Anand. 2020. Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration. In PLoS genetics, 16, e1009259. doi:10.1371/journal.pgen.1009259. https://pubmed.ncbi.nlm.nih.gov/33362196/

8. Marichal, Thomas, Gaudenzio, Nicolas, El Abbas, Sophie, Tsai, Mindy, Galli, Stephen J. 2016. Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. In The Journal of clinical investigation, 126, 4497-4515. doi:10.1172/JCI86359. https://pubmed.ncbi.nlm.nih.gov/27820702/