Rps6ka2, also known as p90 ribosomal S6 kinase-3 (p90 Rsk-3), is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway [3]. It plays a role in various biological processes and is associated with multiple diseases.

In a mouse model of knee osteoarthritis (OA), Nuclease technology-mediated Rps6ka2 knockout in iMSC (induced mesenchymal stem cells) showed that Rps6ka2 could promote iMSC proliferation and chondrogenic differentiation in vitro. In vivo, it improved iMSC viability, promoted extracellular matrix (ECM) production, and attenuated OA [1].

In ovarian cancer, bioinformatic analysis identified Rps6ka2 as a prognosis-related gene. Its expression was down-regulated in ovarian cancer tissues. Overexpression of Rps6ka2 suppressed cell proliferation, while knockdown had the opposite effect, and it was regulated by miRNAs and circRNAs and affected the p38/MAPK signaling pathway [2].

In sporadic epithelial ovarian cancer, Rps6ka2 was considered a putative tumour suppressor gene. Homozygous deletions were found in some cell lines, and re-expression of Rps6ka2 in ovarian cancer cell lines suppressed colony formation, reduced proliferation, caused G1 arrest, and increased apoptosis [3].

In colorectal cancer, Rps6ka2 inhibited the proliferation, migration, and invasion of CRC cells by interacting with PCSK9 and suppressing the PCSK9/MAPK signaling pathway [4].

In pancreatic cancer, a kinome-wide siRNA-based loss-of-function screen identified Rps6ka2 as a modifier of epidermal growth factor receptor (EGFR) activity. Inhibition of Rps6ka2 synergistically enhanced the effect of the EGFR inhibitor erlotinib on tumor cell survival [5].

In conclusion, Rps6ka2 plays important roles in multiple disease conditions such as knee osteoarthritis, ovarian cancer, sporadic epithelial ovarian cancer, colorectal cancer, and pancreatic cancer. Gene knockout models in mice or loss-of-function experiments in cell lines have been crucial in revealing its functions in promoting cell proliferation, chondrogenic differentiation, and its roles in tumor suppression or growth regulation through various signaling pathways. These findings contribute to understanding the biological mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Zhang, Juan, Liao, Jin-Qi, Wen, Li-Ru, Yang, Jian-Hua, Zhou, Guang-Qian. 2023. Rps6ka2 enhances iMSC chondrogenic differentiation to attenuate knee osteoarthritis through articular cartilage regeneration in mice. In Biochemical and biophysical research communications, 663, 61-70. doi:10.1016/j.bbrc.2023.04.049. https://pubmed.ncbi.nlm.nih.gov/37119767/

2. Fu, Zhiqin, Ding, Chao, Gong, Wangang, Lu, Chao. 2023. ncRNAs mediated RPS6KA2 inhibits ovarian cancer proliferation via p38/MAPK signaling pathway. In Frontiers in oncology, 13, 1028301. doi:10.3389/fonc.2023.1028301. https://pubmed.ncbi.nlm.nih.gov/36741009/

3. Bignone, P A, Lee, K Y, Liu, Y, Mungall, A J, Ganesan, T S. 2006. RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer. In Oncogene, 26, 683-700. doi:. https://pubmed.ncbi.nlm.nih.gov/16878154/

4. Wang, Yu, Wang, Yuting, Gao, Huabin, Shi, Huijuan, Han, Anjia. 2025. Ezetimibe mediated RPS6KA2 inhibits colorectal cancer proliferation via PCSK9/MAPK signaling pathway. In Cancer treatment and research communications, 43, 100899. doi:10.1016/j.ctarc.2025.100899. https://pubmed.ncbi.nlm.nih.gov/40112524/

5. Milosevic, Nada, Kühnemuth, Benjamin, Mühlberg, Leonie, Gress, Thomas, Michl, Patrick. . Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. In Neoplasia (New York, N.Y.), 15, 1354-62. doi:. https://pubmed.ncbi.nlm.nih.gov/24403857/