ARHGAP29, a Rho GTPase-activating protein, plays a crucial role in regulating the RhoA GTPase cycle. It acts as a negative regulator of RhoA, controlling the cycling between its active GTP-bound and inactive GDP-bound forms, which is essential for various cellular functions. It is involved in multiple signaling pathways, such as the YAP/TAZ-ARHGAP29-RhoA axis in podocytes, and is associated with biological processes like cell proliferation, migration, and adhesion. Genetic models, including gene knockout models, have been instrumental in studying its functions [1-7].

In podocytes, loss of EPB41L5 (Yurt) led to impaired mechanotransduction via the YAP/TAZ signaling pathway, and ARHGAP29 was identified as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes [1]. In keratinocytes, ARHGAP29 knockdown cells showed increased filamentous actin, phospho-myosin light chain, cell area, and population doubling time, along with significant delays in scratch wound closure in migration assays, indicating its requirement for keratinocyte morphology, proliferation, and migration mediated through the RhoA pathway [2]. In uveal melanoma, EHMT2 suppresses ARHGAP29 transcription in a methyltransferase-dependent pattern in GNAQ/11-mutant cells, leading to elevated RhoA activity and promoting tumorigenesis [3]. In breast cancer cells, knockdown of ARHGAP29 reduced invasion, and its expression was correlated with clinical tumor parameters [4,5]. In prostate cancer, upregulation of ARHGAP29 promoted cell proliferation and invasion, while knockdown had the opposite effect, and it was an independent prognostic factor for biochemical progression-free survival [6]. In a murine model, a loss-of-function mutation in Arhgap29 was associated with embryonic lethality and abnormal oral epithelial adhesions during craniofacial development [7].

In conclusion, ARHGAP29 is essential for multiple cellular functions including proliferation, migration, and adhesion across various cell types. Its role in disease-related processes such as glomerular disease, skin cell function, cancer development, and craniofacial development has been revealed through model-based research. The use of KO/CKO mouse models has been particularly valuable in understanding these functions and their implications in disease areas.

References:

1. Rogg, Manuel, Maier, Jasmin I, Helmstädter, Martin, Schilling, Oliver, Schell, Christoph. 2023. A YAP/TAZ-ARHGAP29-RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions. In Cells, 12, . doi:10.3390/cells12131795. https://pubmed.ncbi.nlm.nih.gov/37443829/

2. Reeb, Tanner, Rhea, Lindsey, Adelizzi, Emily, Dunnwald, Elliot, Dunnwald, Martine. 2023. ARHGAP29 is required for keratinocyte proliferation and migration. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.01.30.525978. https://pubmed.ncbi.nlm.nih.gov/36778214/

3. Li, Yongyun, Zhu, Tianyu, Yang, Jie, Zhang, Jianming, Fan, Xianqun. 2023. EHMT2 promotes tumorigenesis in GNAQ/11-mutant uveal melanoma via ARHGAP29-mediated RhoA pathway. In Acta pharmaceutica Sinica. B, 14, 1187-1203. doi:10.1016/j.apsb.2023.12.002. https://pubmed.ncbi.nlm.nih.gov/38486999/

4. Kolb, Katharina, Hellinger, Johanna, Kansy, Maike, Emons, Günter, Gründker, Carsten. 2020. Influence of ARHGAP29 on the Invasion of Mesenchymal-Transformed Breast Cancer Cells. In Cells, 9, . doi:10.3390/cells9122616. https://pubmed.ncbi.nlm.nih.gov/33291460/

5. Kansy, Maike, Wert, Katharina, Kolb, Katharina, Gallwas, Julia, Gründker, Carsten. . ARHGAP29 Is Involved in Increased Invasiveness of Tamoxifen-resistant Breast Cancer Cells and its Expression Levels Correlate With Clinical Tumor Parameters of Breast Cancer Patients. In Cancer genomics & proteomics, 21, 368-379. doi:10.21873/cgp.20454. https://pubmed.ncbi.nlm.nih.gov/38944420/

6. Shimizu, Kosuke, Matsumoto, Hiroaki, Hirata, Hiroshi, Furutani-Seiki, Makoto, Matsuyama, Hideyasu. 2020. ARHGAP29 expression may be a novel prognostic factor of cell proliferation and invasion in prostate cancer. In Oncology reports, 44, 2735-2745. doi:10.3892/or.2020.7811. https://pubmed.ncbi.nlm.nih.gov/33125156/

7. Paul, B J, Palmer, K, Sharp, J C, Murray, S A, Dunnwald, M. 2017. ARHGAP29 Mutation Is Associated with Abnormal Oral Epithelial Adhesions. In Journal of dental research, 96, 1298-1305. doi:10.1177/0022034517726079. https://pubmed.ncbi.nlm.nih.gov/28817352/