MYL9, the regulatory light chain of myosin, is essential for cell movement by activating myosin motility. It has been shown that MYL9 promotes cancer cell migration and is implicated in tumor development and progression. Interestingly, MYL9 has also been found to interact with CD69, an early activation marker of lymphocytes. This interaction enables the recruitment of T cells to the inflamed lung, which is significant in understanding immune responses [1].
Moreover, the MYL9-CD69 system depletes effector T cells in the tumor microenvironment, weakening the anti-tumor immune response. By disrupting the interaction between MYL9 and CD69, researchers found that it can potentially boost the anti-tumor immune response, make MYL9 an attractive target for cancer immunotherapy [2]. Considering its association with the myosin motors family, MYL9 holds promise as a novel drug target for cancer immunotherapy!
Myosins are conserved proteins that serve as actin-dependent molecular motors, playing important roles in the cytoskeleton. They make up 15%-25% of total body proteins and are mainly found in smooth muscle. The diverse human myosins family consists of 12 classes (I-XII) with 40 identified myosin genes. Myosin's molecular structure includes heavy chains (MHC) and light chains (MLC), which are further classified into basic MLC (MLC I) and regulatory MLC (MLC II). Functionally, myosin motors have emerged as powerful players that drive cytoplasmic streaming, actin organization, and cell expansion (Figure 1) [3-6].
MYL9, also known as MLC2, MRLC1, or MLC-2C, is an important component of myosin. The human MYL9 gene is located on chromosome 20q11.23 and consists of 8621 bases, with 8 introns and 17 exons. It encodes the 20KD myosin regulatory light chain. Myosin is composed of the head, neck, and tail regions. The head has ATP-binding and actin-binding sites for ATP hydrolysis, energy release, and actin binding. The neck contains an alpha helix entwined by two regulatory light chains that bind to myosin light chains and calmodulin. The tail forms a coiled helical structure with hydroxyl groups (Figure 2) [7].
MYL9 is expressed extensively in both normal and tumor tissues, including muscle tissue, visceral tissue, lung cancer, and prostate cancer, etc. Numerous studies have demonstrated that MYL9, as a crucial member of the myosin family, participates in various organismal functions regulated by diverse factors. These functions encompass muscle movement, cell migration, endocytosis, mitosis, signal transduction, and notably, the migration and proliferation of tumor cells [8-11].
Figure 2. MYL9 is a power player in the myosins [7]
MYL9 exerts regulatory functions through two major systems: the Rho-kinase (ROCK) system and the myosin light chain kinase (MLCK) system. Additionally, several other important molecules such as calmodulin-dependent protein kinase II, ILK, PKA, ZIPK, PKC, and the inhibitory molecule CP17 of myosin light chain phosphatase MLCP are also involved [12-14].
As shown in Figure 3, the MLCK and ROCK systems are activated by Ca2+, which leads to an increase in intracellular Ca2+ levels. This activation triggers the activation of myosin light chain myosin. Specifically, ROCK acts as a substrate for myosin light chain, facilitating the phosphorylation and dephosphorylation of the MYL9 gene. Besides, ROCK promotes the elevation of intracellular Ca2+ concentration, which activates MLCK [12].
Phosphorylating MYL9 improves the interaction between myosin and actin, as well as enhances ATPase activity in the myosin light chain head. This leads to cytoskeletal remodeling and boosts cellular capabilities in proliferation, differentiation, adhesion, and migration. The RhoA inhibitory factor effectively hinders the downstream effector protein Rock, thereby inhibiting MYL9 expression and phosphorylation. Consequently, it suppresses actin formation, tumor invasion, metastasis, and tumor cell growth [12].
Figure 3. MYL9 plays a regulatory role through MLCK and ROCK systems [12]
Numerous studies have shown that MYL9 regulates ATPase activity and myosin contraction through phosphorylation and dephosphorylation. Abnormal expression of MYL9, which is associated with cell motility. Various investigations have reported the functions of MYL9 in cell motility is linked to tumor pathogenesis, with effects ranging from tumor suppression to tumor promotion [15-17].
MYL9 is increased in various tumors and contributes to tumor invasion in breast, liver, and glioblastoma cancers. It enhances tumor cell motility in breast and liver cancers [18-19]. In glioblastoma, higher MYL9 expression and phosphorylation levels are associated with poor prognosis and recurrent cases [8]. Pancreatic ductal adenocarcinoma and ovarian epithelial tumors also show increased MYL9 expression. Clinical analysis suggests that MYL9 could be an independent prognostic factor in these tumors [14, 20].
Similarly, MYL9 is significantly upregulated in esophageal squamous cell carcinoma and is associated with poorer overall survival and recurrence-free survival in patients with high MYL9 expression [21]. It also contributes to the progression of osteosarcoma [22]. These findings suggest that MYL9 enhances tumor cell motility, potentially affecting tumor growth and metastasis. Moreover, MYL9 shows promise as a prognostic marker and therapeutic target for various types of tumors.
In contrast, in prostate tissue, MYL9 protein expression was decreased and correlated with age, pathological stage, metastasis, and PSA levels [23]. Similarly, downregulation of MYL9 expression was found in bladder and gastric cancers [24-25]. However, cellular experiments revealed that MYL9 deficiency reduced proliferation and increased apoptosis in gastric cancer cells [15]. In human colorectal cancer, both MYL9 expression and phosphorylation levels were reduced [26]. Upregulating MYL9 inhibited tumor cell proliferation, invasion, and migration while promoting apoptosis in colon cancer stem cells [27-28].
Low MYL9 expression may be associated with non-small cell lung cancer development and metastasis [29-30]. In breast cancer, increased MYL9 reduces cancer cell motility [15]. However, conflicting reports suggest that MYL9 expression at the molecular level may enhance breast cancer cell migration [15, 31]. Thus, the role of MYL9 in malignancy remains controversial, and its involvement in tumors is multifaceted. This complexity underscores the potential value of MYL9 as a valuable marker for therapeutic targeting and prognostic assessment.
Apart from its role in tumors, MYL9 is also implicated in cardiovascular, inflammatory, and neurological diseases [32-35]. Studies on atherosclerosis models have shown that MYL9 expression is significantly downregulated as plaque increases. MYL9 is influenced by angiotensin II (Angiotensin II/AGT) and cytokines such as PDGF-BB. Angiotensin II and PDGF-BB are crucial cytokines that promote smooth muscle cell proliferation and migration during vascular injury. Therefore, MYL9 may have an important role in the development of atherosclerosis [36-37].
Successive reports suggested that MYL9 serves as a new ligand for CD69, crucially involved in regulating immune responses [2, 38-41]. Blocking the interaction between MYL9 and CD69 has demonstrated improvement in allergic respiratory inflammation, such as asthma [2]. During inflammation, vascular damage, and platelet activation, MYL9 network structures and coagulation factors are produced. This leads to the binding of MYL9 to CD69+T cells, resulting in the aggregation of immune cells at the sites of inflammation. Consequently, effector cytokines and chemokines are generated, effectively triggering the activation of the immune response (Figure 4) [41].
Figure 4. The MYL9-CD69 system plays a role in immune response [42]
MYL9 is overexpressed in various cancers and associated with poor prognosis. It may act as a ligand for CD69, promoting the retention of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. This chronic stimulation by tumor antigens leads to T-cell failure. Therefore, targeting the MYL9/CD69 interaction shows promise for cancer immunotherapy due to the important role of antigen-specific CTLs in defending against tumors.
Currently, the clinical experience with MYL9 in cancer treatment is limited. However, mounting evidence supports its potential as a therapeutic target for various tumor treatments. Consequently, MYL9 holds significant clinical application as a molecular marker and potential target for early diagnosis, prognosis prediction, and targeted therapy of tumors.
To fully support researchers and pharmaceutical companies in their research on MYL9 in tumors or other diseases, CUSABIO presents MYL9 protein to support your research on the mechanism of MYL9 or its potential clinical value (click for the full list of MYL9 products: MYL9 Proteins; MYL9 antibodies).
Recombinant Human Myosin regulatory light polypeptide 9(MYL9) (Active) (Code: CSB-YP015318HU)
The greater than 95% as determined by SDS-PAGE.(Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human MYL9 at 2μg/mL can bind Anti-MYL9 recombinant antibody (CSB-RA015318MA1HU), the EC50 is 4.628-6.430 ng/mL.
References
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