2020
DOI: 10.1002/1878-0261.12804
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Rho‐associated protein kinase‐dependent moesin phosphorylation is required for PD‐L1 stabilization in breast cancer

Abstract: Expression of programmed cell death ligand (PD-L1) is associated with poor prognosis in breast cancer. Understanding the regulation of PD-L1 expression in breast cancer could provide a new strategy for breast cancer treatment. Here, we demonstrate that moesin (MSN) phosphorylation by Rho-associated protein kinase (ROCK) stabilizes PD-L1 protein levels. Our results indicate that phosphorylated MSN may compete with the E3 ubiquitin ligase SPOP for binding PD-L1. ROCK inhibition via the Y-27632 inhibitor or MSN s… Show more

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Cited by 30 publications
(32 citation statements)
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“…Furthermore, the fact that the phosphorylated ERM proteins also colocalize with the T cell receptor (TCR) αβ, a member of the immunoglobulin superfamily, and the actin filaments [ 58 ] appears to indicate that crosslinking the TCR complex to the actin cytoskeleton is a novel function of the ERM proteins. Meng et al recently used co-immunoprecipitation assays to demonstrate that moesin physiologically interacts with PD-L1 and is necessary for the stabilization of PD-L1 on the cell surface of human breast cancer cells [ 45 ]. Our immunoprecipitation assay demonstrated, for the first time, that the physiological interaction between PD-L1 and the ERM proteins involved higher amounts of ezrin and radixin but lower amounts of moesin.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Furthermore, the fact that the phosphorylated ERM proteins also colocalize with the T cell receptor (TCR) αβ, a member of the immunoglobulin superfamily, and the actin filaments [ 58 ] appears to indicate that crosslinking the TCR complex to the actin cytoskeleton is a novel function of the ERM proteins. Meng et al recently used co-immunoprecipitation assays to demonstrate that moesin physiologically interacts with PD-L1 and is necessary for the stabilization of PD-L1 on the cell surface of human breast cancer cells [ 45 ]. Our immunoprecipitation assay demonstrated, for the first time, that the physiological interaction between PD-L1 and the ERM proteins involved higher amounts of ezrin and radixin but lower amounts of moesin.…”
Section: Discussionmentioning
confidence: 99%
“…The members of the ezrin/radixin/moesin (ERM) protein family act as crosslinkers between the actin cytoskeleton and several plasma membrane proteins, such as drug transporters for anticancer agents, including P-glycoprotein (P-gp), multidrug resistance protein (MRP)-2, and MRP-3 [ 38 , 39 , 40 , 41 ], as well as other transmembrane proteins involved in cancer progression, including epidermal growth factor receptor 2, several receptor kinases, and cluster of differentiation (CD) 20 [ 42 , 43 , 44 ]. Interestingly, gene silencing of moesin greatly reduces the plasma membrane localization of PD-L1 in a human breast cancer cell line, implying a novel role of moesin in modulating the protein expression levels of PD-L1 via post-translational modification [ 45 ]. However, it remains unclear whether the ERM proteins also regulate the plasma membrane localization of PD-L1 in other cancer cell types.…”
Section: Introductionmentioning
confidence: 99%
“…In addition, Ghosh et al demonstrated that phosphorylated ERM family proteins colocalize with T-cell receptor (TCR) αβ, a member of the immunoglobulin (IgG) superfamily proteins, and actin filaments, implying a novel role of ERM in crosslinking the TCR complex to the actin cytoskeleton [ 56 ]. Recently, Meng et al also confirmed that moesin interacts with PD-L1, and that phosphorylation of moesin is necessary for PD-L1 to stabilize on the cell surface membrane in human breast cancer cell lines [ 40 ]. Our present immunoprecipitation analysis demonstrated that not only moesin but also ezrin and radixin physiologically interacted with PD-L1 and the triple complex of PD-L1, ERM, and actin cytoskeleton.…”
Section: Discussionmentioning
confidence: 99%
“…In fact, a growing body of evidence suggests that ERM proteins post-translationally regulate the plasma membrane localization and functional activity of some drug transporters, including P-glycoprotein (P-gp), multidrug resistant protein (MRP)-2, and MRP-3 [ 33 , 34 , 35 , 36 ], as well as certain cancer-related proteins, such as epidermal growth factor receptor (EGFR) 2, several receptor kinases, and cluster of differentiation (CD) 20 [ 37 , 38 , 39 ] through the direct molecular interaction. Interestingly, gene silencing of moesin has been reported to remarkably decrease the plasma membrane localization of PD-L1 in human breast cancer, indicating a novel regulatory mechanism by which moesin modulates the protein expression levels of PD-L1 via post-translational modification [ 40 ]. However, it is unclear whether ERM proteins also regulate the plasma membrane localization of PD-L1 in other cancer cell types.…”
Section: Introductionmentioning
confidence: 99%
“…In general, these indicate that increasing the infiltration of immune lymphocytes by changing the polarity of cancer cells is only one mechanism, a more complete mechanism remains to be studied. However, there are still something interesting, a study in breast cancer indicated that the phosphorylation of moesin was necessary for programmed cell death-Ligand 1 (PD-L1) to stabilize on the cell membrane surface and silencing moesin can promote T cell activation in vitro and in vivo [ 28 ]. This suggests that in different cancers, the role of moesin may be different, research on different cancer models is conducive to the formulation of personalized clinical treatment plans.…”
Section: Discussionmentioning
confidence: 99%