PRRG4, the proline rich γ -carboxyglutamic acid protein 4, is a transmembrane protein with an extracellular γ -carboxyglutamic acid (Gla) domain and cytosolic WW binding motifs. It has been associated with multiple biological processes and disease-related pathways. PRRG4 may be involved in axon guidance as it is a functional homologue of the Drosophila commissureless (comm) gene, which could potentially contribute to the autistic symptoms of WAGR syndrome [5]. Also, it participates in cancer-related pathways, influencing processes like cell migration, invasion and mitochondrial function [1,2,3,4,6,7].

In breast cancer, PRRG4 knockdown decreased the transcript levels of mitochondrial protein-encoding genes. It was found that PRRG4, via the Src-STAT3-POLG axis, increased mitochondrial DNA content, mitochondrial ATP production, and oxygen consumption, and promoted migratory behaviors of breast cancer cells [1]. Additionally, in breast cancer, PRRG4 promoted metastasis by recruiting the E3 ubiquitin ligase NEDD4, which led to the ubiquitination and degradation of Robo1, a tumor suppressor, and also interacted with and enhanced the activation of Src and FAK [2]. In colorectal cancer, circ_0056618 enhanced PRRG4 expression by competitively binding to miR-411-5p, promoting the malignant progression of the cancer [3]. In endometriosis, LncRNA HOTAIR regulated the invasion and migration of endometrial stromal cells through the miR-519b-3p/PRRG4 pathway [4]. In papillary thyroid carcinoma, circSEMA6A upregulated PRRG4 by targeting miR-520h and recruiting ELAVL1, affecting cell invasion and migration [6]. And a long non-coding RNA lncPRRG4-4, mapped to the same region as PRRG4, promoted viability, cell cycle, migration, and invasion in lung cancer cells [7].

In summary, PRRG4 plays crucial roles in multiple biological processes, especially in cancer development and progression, influencing cell migration, invasion, and mitochondrial function. The studies using loss-of-function models in various cancer types have revealed its significant impact on these disease-related cellular behaviors, providing potential targets for treating metastatic cancers such as breast cancer [1,2].

References:

1. Wang, Yang, Wang, Jieyi, Chen, Lan, Li, Hongzhi, Gu, Haihua. 2023. PRRG4 regulates mitochondrial function and promotes migratory behaviors of breast cancer cells through the Src-STAT3-POLG axis. In Cancer cell international, 23, 323. doi:10.1186/s12935-023-03178-0. https://pubmed.ncbi.nlm.nih.gov/38102641/

2. Zhang, Lingling, Qin, Yaqian, Wu, Guang, Li, Hongzhi, Gu, Haihua. 2020. PRRG4 promotes breast cancer metastasis through the recruitment of NEDD4 and downregulation of Robo1. In Oncogene, 39, 7196-7208. doi:10.1038/s41388-020-01494-7. https://pubmed.ncbi.nlm.nih.gov/33037408/

3. Zhang, Bo, Cao, Wenbin, Liu, Yang, Liu, Chunhui, Sun, Bingfu. 2022. Circ_0056618 enhances PRRG4 expression by competitively binding to miR-411-5p to promote the malignant progression of colorectal cancer. In Molecular and cellular biochemistry, 478, 503-516. doi:10.1007/s11010-022-04525-x. https://pubmed.ncbi.nlm.nih.gov/35916967/

4. Bao, Qiufang, Zheng, Qiaomei, Wang, Shaoyu, Tang, Wenlu, Zhang, Bin. 2022. LncRNA HOTAIR regulates cell invasion and migration in endometriosis through miR-519b-3p/PRRG4 pathway. In Frontiers in oncology, 12, 953055. doi:10.3389/fonc.2022.953055. https://pubmed.ncbi.nlm.nih.gov/36338672/

5. Justice, Elizabeth D, Barnum, Sarah J, Kidd, Thomas. 2017. The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. In PLoS genetics, 13, e1006865. doi:10.1371/journal.pgen.1006865. https://pubmed.ncbi.nlm.nih.gov/28859078/

6. Liu, Yachao, Xin, Yunchao, Shang, Xiaoling, Tian, Zedong, Xue, Gang. . CircSEMA6A upregulates PRRG4 by targeting MiR-520h and recruiting ELAVL1 to affect cell invasion and migration in papillary thyroid carcinoma. In Archives of endocrinology and metabolism, 68, e210541. doi:10.20945/2359-4292-2021-0541. https://pubmed.ncbi.nlm.nih.gov/38394156/

7. Wang, Yuanyuan, Gong, Wei, Zhou, Shiyu, Gao, Xingcheng, Lu, Jiachun. 2018. Long Noncoding RNA PRRG4-4 Promotes Viability, Cell Cycle, Migration, and Invasion in Lung Cancer Cells. In DNA and cell biology, 37, 953-966. doi:10.1089/dna.2018.4220. https://pubmed.ncbi.nlm.nih.gov/30362823/