MYL9, also known as myosin regulatory light polypeptide 9, is a light chain isoform that regulates non-sarcomeric myosin. It is involved in various biological processes such as muscle contraction in non-sarcomeric cells. In immune-related pathways, it interacts with CD69, which is an activation marker on leukocytes, forming the CD69-MYL9 system that regulates immune responses [2,6,7].

In disease-related studies, MYL9 has been implicated in multiple cancers. In colorectal cancer, it is predominantly expressed in cancer-associated fibroblasts (CAFs) rather than cancer cells. High MYL9 expression in CAFs is associated with poor survival, M2 macrophage infiltration, and immunosuppressive microenvironment. It regulates the secretion of CCL2 and TGF-β1 by CAFs through binding with IQGAP1 via the ERK 1/2 pathway, promoting CRC progression through the PI3K-AKT pathway [1]. In pancreatic ductal adenocarcinoma, MYL9 is expressed in the cytoplasm and membrane of cancer cells and acts as an independent prognostic factor for overall survival and distant metastasis-free survival [3]. In squamous cervical cancer, MYL9 promotes migration and invasion by enhancing aerobic glycolysis and the JAK2/STAT3 pathway [4]. Also, in CRC, PRPF19, an E3 ubiquitin ligase, enhances the stability of MYL9 via K63-linked ubiquitination, promoting CRC cell migration and invasion [8]. Moreover, MYL9 is identified as a fibroblast-specific biomarker of poorer prognosis in CRC [9]. In addition, in COVID-19, elevated Myl9 reflects Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and can predict disease severity [10].

MYL9 deficiency in mice is neonatal lethal due to abnormalities in the lung, and the muscularis propria of the bladder and intestine, suggesting its importance for the function of smooth muscle cells in these organs [5]. Overall, MYL9 plays crucial roles in normal organ function, immune responses, and is significantly involved in cancer progression and COVID-19 pathogenesis. The study of MYL9 knockout mouse models has provided valuable insights into its functions in these biological processes and disease conditions.

References:

1. Deng, Shenghe, Cheng, Denglong, Wang, Jun, Cao, Yinghao, Cai, Kailin. 2023. MYL9 expressed in cancer-associated fibroblasts regulate the immune microenvironment of colorectal cancer and promotes tumor progression in an autocrine manner. In Journal of experimental & clinical cancer research : CR, 42, 294. doi:10.1186/s13046-023-02863-2. https://pubmed.ncbi.nlm.nih.gov/37926835/

2. Kimura, Motoko Y, Koyama-Nasu, Ryo, Yagi, Ryoji, Nakayama, Toshinori. 2019. A new therapeutic target: the CD69-Myl9 system in immune responses. In Seminars in immunopathology, 41, 349-358. doi:10.1007/s00281-019-00734-7. https://pubmed.ncbi.nlm.nih.gov/30953160/

3. Matsushita, Katsunori, Kobayashi, Shogo, Akita, Hirofumi, Eguchi, Hidetoshi, Ishii, Hideshi. 2021. Clinicopathological significance of MYL9 expression in pancreatic ductal adenocarcinoma. In Cancer reports (Hoboken, N.J.), 5, e1582. doi:10.1002/cnr2.1582. https://pubmed.ncbi.nlm.nih.gov/34821071/

4. Wen, Bin, Luo, Limei, Zeng, Zhaoyang, Luo, Xiping. . MYL9 promotes squamous cervical cancer migration and invasion by enhancing aerobic glycolysis. In The Journal of international medical research, 51, 3000605231208582. doi:10.1177/03000605231208582. https://pubmed.ncbi.nlm.nih.gov/37950670/

5. Huang, Chu-Han, Schuring, Joyce, Skinner, Jarrod P, Mok, Lawrence, Chong, Mark M W. 2022. MYL9 deficiency is neonatal lethal in mice due to abnormalities in the lung and the muscularis propria of the bladder and intestine. In PloS one, 17, e0270820. doi:10.1371/journal.pone.0270820. https://pubmed.ncbi.nlm.nih.gov/35802750/

6. Kimura, Motoko Y, Hayashizaki, Koji, Tokoyoda, Koji, Motohashi, Shinichiro, Nakayama, Toshinori. . Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation. In Immunological reviews, 278, 87-100. doi:10.1111/imr.12559. https://pubmed.ncbi.nlm.nih.gov/28658550/

7. Nakayama, Toshinori, Hirahara, Kiyoshi, Kimura, Motoko Y, Hashimoto, Kahoko, Motohashi, Shinichiro. . CD4+ T cells in inflammatory diseases: pathogenic T-helper cells and the CD69-Myl9 system. In International immunology, 33, 699-704. doi:10.1093/intimm/dxab053. https://pubmed.ncbi.nlm.nih.gov/34427648/

8. Zhou, Rui, Chen, Jie, Xu, Yunxiuxiu, Chen, Tao, Qiu, Lin. 2023. PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9. In Cell death & disease, 14, 258. doi:10.1038/s41419-023-05776-2. https://pubmed.ncbi.nlm.nih.gov/37031206/

9. Zhou, Yuan, Bian, Shuhui, Zhou, Xin, Fu, Wei, Tang, Fuchou. 2020. Single-Cell Multiomics Sequencing Reveals Prevalent Genomic Alterations in Tumor Stromal Cells of Human Colorectal Cancer. In Cancer cell, 38, 818-828.e5. doi:10.1016/j.ccell.2020.09.015. https://pubmed.ncbi.nlm.nih.gov/33096021/

10. Iwamura, Chiaki, Hirahara, Kiyoshi, Kiuchi, Masahiro, Yokote, Koutaro, Nakayama, Toshinori. 2022. Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2203437119. doi:10.1073/pnas.2203437119. https://pubmed.ncbi.nlm.nih.gov/35895716/