RhoBTB3, an atypical Rho GTPase family member, binds and hydrolyzes ATP rather than GTP. It plays essential roles in multiple biological processes, including vesicular trafficking, autophagy, cell cycle regulation, and is associated with various diseases. RhoBTB3 functions in protein transport from endosomes to the trans-Golgi network by interacting with Rab9 GTPase [4]. It is also involved in the biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts as part of the RhoBTB3-SHIP164-Vps26B complex [3].

In disease-related studies, in breast cancer, RhoBTB3 mRNA levels are up-regulated, and its knockdown may inhibit the proliferation, migration, and metastasis of breast cancer cells by repressing Col1a1 expression [1]. In autophagy, RhoBTB3 negatively regulates autophagy by mediating AMBRA1 ubiquitination and degradation [2]. In non-M3 acute myeloid leukemia, high RhoBTB3 expression predicts favorable chemotherapy outcomes [5]. In renal cell carcinoma, miR-142-3p promotes tumor progression by targeting RhoBTB3 to regulate HIF-1 signaling and GGT/GSH pathways [6]. In mice lacking RhoBTB3, there are subtle alterations in platelet alpha-granule secretion and adhesion to collagen without significant effects on hemostasis in vivo [7].

In summary, RhoBTB3 is crucial in vesicular trafficking, autophagy, cell cycle, and has significant implications in diseases such as breast cancer, autophagy-related diseases, non-M3 acute myeloid leukemia, and renal cell carcinoma. The gene knockout mouse model of RhoBTB3 has provided valuable insights into its functions in platelet-related physiological processes and in vivo hemostasis.

References:

1. Kim, Kyungho, Kim, Youn-Jae. 2022. RhoBTB3 Regulates Proliferation and Invasion of Breast Cancer Cells via Col1a1. In Molecules and cells, 45, 631-639. doi:10.14348/molcells.2022.2037. https://pubmed.ncbi.nlm.nih.gov/35698915/

2. Kim, Kyungho, Kim, Dong-Gun, Kim, Youn-Jae. 2024. RhoBTB3 Functions as a Novel Regulator of Autophagy by Suppressing AMBRA1 Stability. In Cells, 13, . doi:10.3390/cells13191659. https://pubmed.ncbi.nlm.nih.gov/39404422/

3. Wang, Jingru, Xiong, Juan, Zhang, Shuhan, Deng, Lin, Ji, Wei-Ke. 2024. Biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts by the RhoBTB3-SHIP164-Vps26B complex. In Cell discovery, 10, 38. doi:10.1038/s41421-024-00651-6. https://pubmed.ncbi.nlm.nih.gov/38565878/

4. Espinosa, Eric J, Calero, Monica, Sridevi, Khambhampaty, Pfeffer, Suzanne R. . RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport. In Cell, 137, 938-48. doi:10.1016/j.cell.2009.03.043. https://pubmed.ncbi.nlm.nih.gov/19490898/

5. Yang, Shuang-Hui, Liu, Wei, Peng, Jie, Chen, Cong, Liu, En-Yi. 2021. High Expression of RhoBTB3 Predicts Favorable Chemothrapy Outcomes in non-M3 Acute Myeloid Leukemia. In Journal of Cancer, 12, 4229-4239. doi:10.7150/jca.50472. https://pubmed.ncbi.nlm.nih.gov/34093823/

6. Zhang, Yijing, Ma, Sha, Zhang, Jun, Cao, Xiliang, Wei, Jin. 2023. MicroRNA-142-3p promotes renal cell carcinoma progression by targeting RhoBTB3 to regulate HIF-1 signaling and GGT/GSH pathways. In Scientific reports, 13, 5935. doi:10.1038/s41598-022-21447-2. https://pubmed.ncbi.nlm.nih.gov/37045834/

7. Berger, Martin, Lutz, David R J, Lutz, Julia, Naseem, Khalid M, Rivero, Francisco. 2019. Alterations in Platelet Alpha-Granule Secretion and Adhesion on Collagen under Flow in Mice Lacking the Atypical Rho GTPase RhoBTB3. In Cells, 8, . doi:10.3390/cells8020149. https://pubmed.ncbi.nlm.nih.gov/30754723/