Rab1a, a small GTPase, is well-known for its role in vesicular trafficking. It also participates in eukaryotic secretion, autophagy, and intracellular traffic, and is involved in the regulation of the mTORC1-S6K, amino acids-mTORC1, and Hedgehog pathways [1,2,4]. Rab1a is essential for maintaining normal physiological functions, with its dysregulation linked to various diseases [1-10]. Genetic models, especially knockout mouse models, have been crucial in understanding its functions in vivo [2,5].

In a whole-body Rab1A knockout (Rab1A-/-) mouse model, adult mice became hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation, revealing the role of Rab1A in whole-body glucose homeostasis through mediating AA-mTORC1 signaling [2]. In another study, disruption of the Rab1a gene in mice led to early embryonic lethality, indicating its essentiality for early mouse embryo development [5]. In the context of disease, in osteoarthritis, inhibition of Rab1a attenuated cartilage matrix degradation and cell apoptosis, while its overexpression exacerbated these processes, with Rab1a suppressing autophagy via activation of the mTORC1-S6K pathway [1]. In cancer, high Rab1A expression was associated with poor prognosis, adverse clinicopathological parameters, and promotion of cell proliferation, migration, and metastasis in various cancer types such as colorectal, non-small cell lung, and nasopharyngeal cancers [3,4,6,7].

In summary, Rab1a plays a vital role in embryonic development, glucose homeostasis, and autophagy regulation. Mouse knockout models have been instrumental in uncovering its functions in these processes and in understanding its contributions to diseases like diabetes, osteoarthritis, and cancer. The study of Rab1a provides potential therapeutic targets for these diseases.

References:

1. Chen, Ze, Tang, Mingze, Wu, Zewei, Ding, Changhai, Han, Weiyu. 2024. Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway. In Journal of advanced research, , . doi:10.1016/j.jare.2024.11.009. https://pubmed.ncbi.nlm.nih.gov/39521431/

2. Zhang, Xin, Wang, Xiaowen, Yuan, Ziqiang, Libutti, Steven K, Zheng, X F Steven. . Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis. In Cell reports, 34, 108830. doi:10.1016/j.celrep.2021.108830. https://pubmed.ncbi.nlm.nih.gov/33730578/

3. Wang, Jingjing, Liao, Jianhua, Liu, Jingting, Liu, Baoqing, Shao, Chaodan. . Analysis of Correlation between Rab1A Expression and its Prognosis in Cancers: a Meta-Analysis. In Clinical laboratory, 70, . doi:10.7754/Clin.Lab.2023.230660. https://pubmed.ncbi.nlm.nih.gov/38213209/

4. Peng, Chaozhong, Li, Xiao, Ye, Zhixue, Wu, Wenqing. 2021. Rab1A promotes cell proliferation and migration by upregulating Gli1 in colorectal cancer. In Scientific reports, 11, 16243. doi:10.1038/s41598-021-95798-7. https://pubmed.ncbi.nlm.nih.gov/34376787/

5. Wu, Yin, Yang, Darong, Chen, Guo-Yun. 2022. Targeted disruption of Rab1a causes early embryonic lethality. In International journal of molecular medicine, 49, . doi:10.3892/ijmm.2022.5101. https://pubmed.ncbi.nlm.nih.gov/35137917/

6. Huang, Tinglei, Chen, Biying, Wang, Feng, Jiang, Bin, Zhang, Yanjie. 2021. Rab1A promotes IL-4R/JAK1/STAT6-dependent metastasis and determines JAK1 inhibitor sensitivity in non-small cell lung cancer. In Cancer letters, 523, 182-194. doi:10.1016/j.canlet.2021.10.008. https://pubmed.ncbi.nlm.nih.gov/34627950/

7. Yang, Xian-Zi, Chen, Xi-Min, Zeng, Li-Si, Wang, Hui-Yun, Cui, Shu-Zhong. 2020. Rab1A promotes cancer metastasis and radioresistance through activating GSK-3β/Wnt/β-catenin signaling in nasopharyngeal carcinoma. In Aging, 12, 20380-20395. doi:10.18632/aging.103829. https://pubmed.ncbi.nlm.nih.gov/33068388/