Gabarapl1-KO Mouse

Gabarapl1, also known as GABA type A receptor associated protein like 1, was first described as an early estrogen-regulated gene. It belongs to the GABARAP family and shares high sequence homology with GABARAP. Gabarapl1, similar to GABARAP, interacts with the GABAA receptor and tubulin, promoting tubulin polymerization. The GABARAP family members are involved in protein/vesicle transport, autophagy, cell death, cell proliferation, and tumor progression [1].

In lung adenocarcinoma, EMT induction led to increased Gabarapl1 expression via SMAD signaling, and Gabarapl1 knockout induced EMT due to defective SMAD protein degradation, suggesting it intervenes in an EMT-regulatory loop [2]. In AR-positive prostate cancer, Gabarapl1 knockdown inhibited cell growth, decreased AR/AR-V transcription activity and nuclear translocation [3]. In HNSCC, Gabarapl1 knockdown inhibited EGFR membrane expression during hypoxia, indicating its role in EGFR trafficking [4]. In breast cancer, Gabarapl1-deficient tumors had a decreased number of pulmonary metastases, showing its essentiality in metastasis development [5]. In prostate cancer, Gabarapl1 knockdown increased invasion and lymph node metastasis, while its over-expression decreased invasiveness, and Akt phosphorylation was negatively correlated with Gabarapl1 expression, suggesting that the suppression of FOXOs-Gabarapl1 signaling by Akt is a mechanism for prostate cancer progression and metastasis [6].

In summary, Gabarapl1 plays crucial roles in multiple biological processes and disease conditions. Its functions in processes like EMT, cancer cell growth, metastasis, and protein trafficking have been revealed through gene knockdown and knockout studies in various cancer models. These findings contribute to understanding the mechanisms of diseases such as lung, prostate, and breast cancers, providing potential therapeutic targets for these malignancies.

References:

1. Le Grand, Jaclyn Nicole, Chakrama, Fatima Zahra, Seguin-Py, Stéphanie, Jouvenot, Michèle, Boyer-Guittaut, Michaël. 2011. GABARAPL1 (GEC1): original or copycat? In Autophagy, 7, 1098-107. doi:10.4161/auto.7.10.15904. https://pubmed.ncbi.nlm.nih.gov/21597319/

2. Jacquet, Marine, Hervouet, Eric, Baudu, Timothée, Fraichard, Annick, Despouy, Gilles. 2021. GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback. In Biology, 10, . doi:10.3390/biology10100956. https://pubmed.ncbi.nlm.nih.gov/34681055/

3. Su, Bing, Zhang, Lijuan, Liu, Shenglin, Chen, Xiaofan, Zhang, Wei. 2019. GABARAPL1 Promotes AR+ Prostate Cancer Growth by Increasing FL-AR/AR-V Transcription Activity and Nuclear Translocation. In Frontiers in oncology, 9, 1254. doi:10.3389/fonc.2019.01254. https://pubmed.ncbi.nlm.nih.gov/31803623/

4. Keulers, Tom G, Schaaf, Marco B E, Peeters, Hanneke J M, Jutten, Barry, Rouschop, Kasper M A. 2015. GABARAPL1 is required for increased EGFR membrane expression during hypoxia. In Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 116, 417-22. doi:10.1016/j.radonc.2015.06.023. https://pubmed.ncbi.nlm.nih.gov/26164772/

5. Beaumont, Joel E J, Ju, Jinzhe, Barbeau, Lydie M O, Keulers, Tom G H, Rouschop, Kasper M A. 2023. GABARAPL1 is essential in extracellular vesicle cargo loading and metastasis development. In Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 190, 109968. doi:10.1016/j.radonc.2023.109968. https://pubmed.ncbi.nlm.nih.gov/37898438/

6. Su, Wei, Li, Shibao, Chen, Xiaofan, Ma, Yingyu, Su, Bing. . GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer. In Oncotarget, 8, 4449-4459. doi:10.18632/oncotarget.13879. https://pubmed.ncbi.nlm.nih.gov/27966458/