Dynamic Regulation of Extracellular Signal-Regulated Kinase (ERK) by Protein Phosphatase 2A Regulatory Subunit B56γ1 in Nuclei Induces Cell Migration

Kawahara, Ei; Maenaka, Shiori; Shimada, Eri; Nishimura, Yoshihiro; Sakurai, Hiroshi

doi:10.1371/journal.pone.0063729

Cited by 14 publications

(17 citation statements)

References 72 publications

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“…However, in the cases with no mutation of EGFR, there is no obvious reason for pERK/IER3 overexpression. Therefore, we considered the possible role of a positive feedback loop of ERK/IER3/ PP2A-B56γ1 in the nucleus (17). Both IER3 and pERK were overexpressed in the nucleus in adenocarcinomas examined by us, which is consistent with the existence of an ERK/IER3/ PP2A-B56γ1-positive feedback loop in lung adenocarcinoma.…”

Section: Discussionsupporting

confidence: 73%

“…IER3 inhibits PP2A-B56γ, resulting in inhibition of ERK dephosphorylation (13,17), so that overexpression of IER3 could result in sustained activation of ERK, leading to cell proliferation. Our immunohistochemical findings that both IER3 and pERK were overexpressed in adenocarcinomas support this idea.…”

Section: Discussionmentioning

confidence: 99%

“…PP2A-B56γ1 dephosphorylates and inactivates ERK, and inhibits cell proliferation and migration (15,17). PP2A functions as a tumor-suppressor gene (38,39).…”

Section: Discussionmentioning

confidence: 99%

“…IER3 regulates ERK activity through its inhibitory activity on B56-containing PP2A, which dephosphorylates ERK (13). Recently it has been clarified that activated ERK induces IER3 protein synthesis, and then IER3 inhibits B56γ1-PP2A, forming the ERK/IER3/B56γ1-PP2A positive feedback loop, which eventually leads to sustained activation of ERK (17). The duration of ERK activation is considered to be one of the factors that determine cellular events (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…All of these findings indicate an important role of B56γ in carcinogenesis. We recently showed that the ERK/IER3/ B56γ1 loop is activated by the growth factor-induced RAS/ RAF/mEK/ERK cascade (17). After growth factor binds to epidermal growth factor receptor (EGFR), RAS, RAF, mEK and ERK are activated sequentially by phosphorylation or binding (26).…”

Section: Introductionmentioning

confidence: 99%

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Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

et al. 2016

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Abstract. In order to investigate the involvement of the IER3/ PP2A-B56γ/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56γ gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas. IntroductionIER3 (immediate early response gene 3) was first identified in fibroblasts from mouse in 1993 (1), and human IER3, formerly referred to as the immediate early gene X-1 (IEX-1), was first identified in human squamous cell carcinomas. The human IER3 gene is located on the short arm of chromosome 6 (6p21.3) and has 2 exons. The gene encodes 156 amino acids (2). IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5-8). However, there has been no study of IER3 expression in human lung carcinoma.Protein phosphatase 2A (PP2A), which consists of structural subunit A, regulatory subunits B, and catalytic subunit C, has a broad spectrum of functions due to the variety of regulatory subunits, of which there are more than 20 kinds (9). PP2A can act as a tumor suppressor (10,11). B56 regulatory subunits are involved in cell proliferation signaling (11,12). Among them, PP2A-B56γ1 dephosphorylates Thr 202 of phosphorylated extracellular signal-regulated kinase (pERK), leading to inactivation of ERK (13). Furthermore, Garcia et al (14) found that the regulation of cell growth by IER3 is mediated by ERK, which also plays a central role in regulation of a variety of cellular events, including cell proliferation, differentiation, migration, and apoptosis (15,16). IER3 regulates ERK activity through its i...

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

“…PP2A-B56γ1 dephosphorylates and inactivates ERK, and inhibits cell proliferation and migration (15,17). PP2A functions as a tumor-suppressor gene (38,39).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

et al. 2016

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Protein phosphatase 2A plays an important role in migration of bone marrow stroma cells

et al. 2015

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Administration of bone marrow stroma cells (BMSCs) has the potential to ameliorate degenerative disorders and to repair injured sites. The homing of transplanted BMSCs to damaged tissues is a critical property of engraftment. Therefore, it is important to understand signal molecules controlling migration of BMSCs. Here, we demonstrate that serine-threonine protein phosphatase 2A (PP2A) is responsive to migration of BMSCs. Pharmacological Inhibition of PP2A, using okadaic acid (OA), leads to attenuated cell migration in rat primary BMSCs both in the absence or presence of stromal cell-derived factor-1 (SDF-1). Consistent with the above findings, knockdown of the main catalytic subunit PP2Acα using small interfering RNA also attenuates chemotaxis of BMSCs. On the other hand, cell viability of BMSCs remains unchanged with OA treatment or knockdown of PP2Acα subunit. Moreover, we observed an upregulation of PP2A-B55β in transcription level after SDF-1 treatment, indicating their potential role as the functioning regulatory subunit of PP2A phosphatase in BMSCs migration model. Collectively, these data provide first insight into the modulation of BMSCs migration by PP2A phosphatase activity and lay a foundation for exploring PP2A signaling as a modulating target for BMSCs transplantation.

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Prognostic Impact of PPP2R5C Gene Expression in Adult Acute Myeloid Leukemia Patients with Normal Cytogenetics

Taweel

Gawdat

Abdelfattah

2019

Indian J Hematol Blood Transfus

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Protein Phosphatase 2A (PP2A) is a crucial regulator of the cellular signalling pathways, proliferation, cell cycle checkpoints and apoptosis. The PPP2R5C gene encodes PP2A regulatory B56c subunit. Malignant transformation may occur, if mRNA of PPP2R5C is functionally deregulated, structurally altered, decreased or overexpressed. Therefore, the purpose of the study was to examine PPP2R5C mRNA expression, evaluate its association with the different clinical and haematological parameters and determine its prognostic impact in Egyptian adult acute myeloid leukaemia patients with normal cytogenetics (CN-AML). Peripheral blood samples of 50 de novo CN-AML patients and 20 age-and gender-matched healthy controls were examined for PPP2R5C expression by Quantitative Real Time-Polymerase Chain Reaction. The expression levels of PPP2R5C mRNA were significantly higher in the CN-AML samples than in the control samples (P B 0.001). There was a statistical significant difference between the low and high expression levels of PPP2R5C with regard to age (P = 0.005, r = -0.447, P = 0.001). The patients with an unfavourable response to induction chemotherapy had significant higher PPP2R5C expression levels than those with a favourable response (P = 0.002). There was a significant influence of high PPP2R5C expression levels on the overall survival and progression free survival (P = 0.03, 0.026), respectively. PPP2R5C overexpression is an adverse prognostic factor which affects leukaemogenesis in the CN-AML, it may predict the disease progression and overall survival during the follow-up of the patients.

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Dynamic Regulation of Extracellular Signal-Regulated Kinase (ERK) by Protein Phosphatase 2A Regulatory Subunit B56γ1 in Nuclei Induces Cell Migration

Cited by 14 publications

References 72 publications

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

Protein phosphatase 2A plays an important role in migration of bone marrow stroma cells

Prognostic Impact of PPP2R5C Gene Expression in Adult Acute Myeloid Leukemia Patients with Normal Cytogenetics

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