Rasgrp3, short for Ras guanylnucleotide releasing peptide 3, is an important signaling protein responsive to diacylglycerol (DAG) that increases Ras activation, integrating DAG and Ras signaling pathways with actin polymerization [2]. It is involved in multiple cellular processes such as cell proliferation, migration, and invasion, and is associated with the MAPK, Akt-MDM2, and EGFR-STAT3 signaling pathways [1,3,4].

Rasgrp3 has been found to play diverse roles in various diseases. In colorectal cancer, down-regulation of lncRNA AC092894.1 promotes oxaliplatin resistance via the USP3/AR/Rasgrp3 axis, as AC092894.1 acts as a scaffold molecule to increase Rasgrp3 transcription [1]. In glioma, Rasgrp3 is up-regulated and promotes cell migration and invasion through interaction with Arp3 [2]. In acute myeloid leukemia, mutant NPM1 maintains Rasgrp3 protein stability, which in turn activates the EGFR-STAT3 axis to promote cell proliferation and autophagy [3]. In papillary thyroid cancer, Rasgrp3 over-expression promotes cell proliferation and migration through Akt-mediated MDM2 activation [4]. In systemic lupus erythematosus, over-expression of Rasgrp3 in peripheral blood mononuclear cells is associated with disease activity [5]. In uveal melanoma, Rasgrp3 mediates MAPK pathway activation in GNAQ mutant tumors [6]. In esophageal squamous cell carcinoma and melanoma, Rasgrp3 contributes to malignant proliferation and aggressiveness [7,8]. In prostate cancer, Rasgrp3 contributes to the formation and maintenance of the cancer phenotype [9].

In conclusion, Rasgrp3 is a crucial signaling protein involved in multiple cellular processes and is associated with the development and progression of various cancers and autoimmune diseases. Understanding the function of Rasgrp3 through in vivo and in vitro studies provides potential therapeutic targets for these diseases [1-10].

References:

1. Zheng, Zhijian, Wu, Ming, Li, Hongyan, Ding, Linchao, Fu, Jianfei. 2023. Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis. In BMC medicine, 21, 132. doi:10.1186/s12916-023-02826-6. https://pubmed.ncbi.nlm.nih.gov/37013584/

2. Lee, Hae Kyung, Finniss, Susan, Cazacu, Simona, Blumberg, Peter M, Brodie, Chaya. . RasGRP3 regulates the migration of glioma cells via interaction with Arp3. In Oncotarget, 6, 1850-64. doi:. https://pubmed.ncbi.nlm.nih.gov/25682201/

3. Wang, Youping, Pan, Chi, Zhang, Xia, Zhao, Aiqi, Dong, Ying. . Mutant NPM1 maintains RASGRP3 protein stability via interaction with MID1 to promote acute myeloid leukemia cell proliferation and autophagy. In Journal of leukocyte biology, 113, 504-517. doi:10.1093/jleuko/qiad023. https://pubmed.ncbi.nlm.nih.gov/36826998/

4. Qiu, Wangwang, Xia, Xiaotian, Qiu, Zhongling, Guo, Minggao, Yang, Zhili. 2017. RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway. In Gene, 633, 35-41. doi:10.1016/j.gene.2017.08.024. https://pubmed.ncbi.nlm.nih.gov/28864115/

5. An, Xiang-Jie, Xia, Ying, Li, Jun, Yang, Liu, Tao, Juan. 2019. RasGRP3 in peripheral blood mononuclear cells is associated with disease activity and implicated in the development of systemic lupus erythematosus. In American journal of translational research, 11, 1800-1809. doi:. https://pubmed.ncbi.nlm.nih.gov/30972203/

6. Chen, Xu, Wu, Qiuxia, Depeille, Philippe, Roose, Jeroen P, Bastian, Boris C. . RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. In Cancer cell, 31, 685-696.e6. doi:10.1016/j.ccell.2017.04.002. https://pubmed.ncbi.nlm.nih.gov/28486107/

7. Zhang, Ziteng, Ma, Ming, Hu, Ronghang, Wei, Haixiang, Meng, Yanhong. 2018. RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma. In Clinical and experimental pharmacology & physiology, 45, 720-728. doi:10.1111/1440-1681.12926. https://pubmed.ncbi.nlm.nih.gov/29461644/

8. Yang, Dazhi, Tao, Juan, Li, Luowei, Yuspa, Stuart H, Blumberg, Peter M. 2011. RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma. In Oncogene, 30, 4590-4600. doi:10.1038/onc.2011.166. https://pubmed.ncbi.nlm.nih.gov/21602881/

9. Yang, Dazhi, Kedei, Noemi, Li, Luowei, Yuspa, Stuart H, Blumberg, Peter M. 2010. RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. In Cancer research, 70, 7905-17. doi:10.1158/0008-5472.CAN-09-4729. https://pubmed.ncbi.nlm.nih.gov/20876802/