Protein phosphatase 1 regulatory subunit 18 suppresses the transcriptional activity of NFATc1 via regulation of c-fos

Abstract

The transcription factor NFATc1 and its binding partner AP-1 (a complex containing c-fos and c-Jun) play a central role in osteoclast differentiation. NFATc1 and AP-1 promote the expression of target genes such as Acp5, Ctsk and also auto-regulate NFATc1 expression as well. We previously reported that protein phosphatase 1 regulatory subunit 18 (PPP1r18) is a negative regulator of osteoclast bone resorption by inhibiting cell attachment to bone matrix. We also reported that PPP1r18 potentially regulates NFATc1 expression during osteoclast differentiation. To further explore this, in this study we have examined the effect of PPP1r18 on NFATc1 expression and activity by overexpressing PPP1r18 during the early stage of osteoclast differentiation. We found that PPP1r18 suppressed NFATc1 expression through inhibition of the transcriptional activity of NFATc1. Since PPP1r18 does not regulate NFATc1 directly, we next explored the involvement of AP-1. Our data showed that c-fos phosphorylation and nuclear localization were reduced by PPP1r18 overexpression. Further experiments showed that overexpression of c-fos together with PPP1r18 rescued NFATc1 expression and transcriptional activity. Moreover, c-fos activity inhibition by PPP1r18 was canceled by mutation of the phosphatase binding site of PPP1r18. Taken together, PPP1r18-regulated phosphatase activity targets c-fos phosphorylation and suppresses subsequent NFATc1 expression and activity.

Tyrosine Kinase Src Is a Regulatory Factor of Bone Homeostasis

“…PPP1r18 expression is considerably reduced during osteoclast differentiation, similar to Cbp levels in osteoclasts and other tissues. In addition, PPP1r18 negatively regulates NFATc1 transactivation by destabilizing c-Fos, which is a complex partner of NFATc1 [ 9 ]. NFATc1 and c-fos are upregulated in lymphoid cells during inflammation as they promote the differentiation and function of immune cells, such as T and B cells [ 44 , 45 ].…”

“…Osteoclasts differentiate from hematopoietic stem cells upon stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL), which are secreted by osteoblasts [ 5 , 6 ]. RANKL binds to the receptor activator of nuclear factor kappa-B (RANK) and activates nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling [ 5 , 7 , 8 , 9 ]. The AP-1 complex consists of c-Jun and c-fos under the MAPK signaling pathway.…”

Long-Term Cardiac Disease- and Cancer-Associated Mortalities in Patients With Non-Metastatic Stomach Adenocarcinoma Receiving Resection and Chemotherapy: A Large Competing-Risk Population-Based Cohort Study

“…Gastric cancer, the majority of which is adenocarcinoma, ranks fifth in cancer incidence and is the fourth leading cause of cancer-related mortality globally, with about 1,089,000 new cases and around 769,000 associated deaths in 2020 [ 1 - 4 ]. While resection remains the mainstay and cornerstone of curative treatment for most non-metastatic gastric adenocarcinoma (nmGaC) [ 5 , 6 ], increasing numbers of patients with nmGaC also receive chemotherapy, based on evidence from major clinical trials [ 7 - 10 ].…”

Survival Prognosis, Tumor Immune Landscape, and Immune Responses of PPP1R18 in Kidney Renal Clear Cell Carcinoma and Its Potentially Double Mechanisms

“…By means of TCGA data mining, protein phosphatase 1 regulatory subunit 18 (PPP1R18) was finally identified by us in KIRC, after a series of gene filtrations including difference analysis, survival analysis, univariate analysis, multivariate analysis, other datasets and polymerase chain reaction (PCR) validations, sequentially. To our knowledge, PPP1R18, also known as HKMT1098, KIAA1949, was reported to be a protein phosphatase 1 (PP1)-binding protein, or an actin-regulatory protein [ 6 , 7 ]. Matsubara et al revealed that PPP1R18 was able to regulate osteoclasts’ bone resorption activity, maturation and actin ring formation [ 6 ].…”

“…Matsubara et al revealed that PPP1R18 was able to regulate osteoclasts’ bone resorption activity, maturation and actin ring formation [ 6 ]. Yasuda et al shed light on that PPP1R18 could suppress the transcriptional activity of NFATc1 to repress osteoclast differentiation at early stage [ 7 ]. As for cancer research, Ha et al identified eight differentially expressed genes above 16-fold changes including PPP1R18, that were significantly related to preoperative chemoradiation therapy responses in rectal cancer [ 8 ].…”