B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer

Tan, Jian; Lee, Puay Leng; Li, Zhimei; Jiang, Xia; Lim, Yong Ching; Hooi, Shing Chuan; Q, Yu

doi:10.1016/j.ccr.2010.10.021

Cited by 101 publications

(106 citation statements)

References 53 publications

(77 reference statements)

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“…Moreover, Hct116 cells contain robust S384 phosphatase activity (Fig. 1C and D) but have been reported not to express the B55␤ isoform due to promoter hypermethylation at the PPP2R2B gene (49). We also confirmed the lack of B55␤ mRNA in Hct116 cells experimentally (Fig.…”

Section: Discussionsupporting

confidence: 76%

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

Davis

Swanger

Hughes

et al. 2017

Molecular and Cellular Biology

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Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCF Fbw7 ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates. We found that S384 phosphorylation is dynamically regulated in cells and that cyclin E is specifically dephosphorylated at S384 by the PP2A-B56 phosphatase, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase but low in mitosis. This provides a mechanism whereby interphase cells can oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity while also enabling cyclin E destruction in mitosis, when inappropriate cyclin E expression is genotoxic.KEYWORDS cell cycle, cyclin-dependent kinases, cyclins, serine/threonine phosphatases, ubiquitination T he mammalian cell cycle is regulated by cyclin-dependent kinases (CDKs) and their associated cyclin regulatory subunits. Cyclin E-CDK2 has essential roles as cells exit quiescence and during endoreduplication. It also regulates numerous processes during the G 1 and S-phases of the cell cycle, including S-phase entry, DNA replication, and centrosome duplication (1-5).Cells must tightly regulate cyclin E-CDK2 activity, and this is accomplished through a variety of mechanisms, including E2F-dependent cyclin E transcription, binding of CDK inhibitor proteins (p27Kip1 and p21Cip1), activating and inhibitory phosphorylation of CDK2, and cyclin E degradation by the ubiquitin-proteasome system (1, 2). Abnormal cyclin E-CDK2 activity disrupts normal G 1 /S control and causes genomic instability (6-12). Importantly, cyclin E is oncogenic in multiple contexts: the cyclin E gene is amplified in human serous ovarian and basal breast cancers, and its deregulated activity promotes tumorigenesis in mice (13-16).The F-box protein Fbw7 is the substrate recognition component of an SCF ubiquitin ligase that targets cyclin E for degradation after cyclin E becomes phosphorylated within conserved motifs called Cdc4 phosphodegrons (CPDs) (17)(18)(19)(20)(21)(22). Fbw7 substrate CPDs contain two negative charges: a phosphorylated-Thr/Ser (pT/S) in the 0 position, and a second pT/S or an acidic amino acid in the ϩ4 position (23,24). Cyclin E contains two CPDs: a high-affinity C-terminal degron that is phosphorylated at T380 and S384 and is the primary determinant of Fbw7 binding and a low-affinity N-terminal degron that contains only one phosphorylation site, at T62 (Fig. 1A). Phosphorylation-

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Section: Discussionsupporting

confidence: 76%

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

Davis

Swanger

Hughes

et al. 2017

Molecular and Cellular Biology

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“…In cancer, PR55β might exert functions similar to those observed in development or differentiation. Indeed, PR55β has been found to be related to colorectal cancer (19). However, the exact relationship between cancer and this specific subunit were previously unclear.…”

Section: Discussionmentioning

confidence: 99%

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Ishibashi

Ishii

Sugiyama

et al. 2018

CGP

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Abstract. Background Adenoid cystic carcinoma (AdCC) is a rare cancer that arises within the secretory glands, mainly the salivary gland. For head and neck AdCC, the age-adjusted incidence rate is 4.5 cases per 100,000 individuals and exhibits a slight female predominance (1). The risks for delayed recurrence and metastasis in other organs are higher in AdCC than in other oral cancers, such as squamous cell carcinoma (SCC), because of the propensity of AdCC to invade neighbouring tissues and migrate into blood vessels (2, 3). Despite the fact that hundreds of malignant AdCC tumors have been characterized at the molecular level, the underlying regulatory mechanisms of this cancer type remain unclear.To date, many clinical AdCC studies have reported that poor prognosis is associated with pathological features such as AdCC type and grade (4). Histological specimens can be divided into three groups: tubular, cribriform, or solid. Because patients with solid AdCC are especially likely to present with distant metastases, they are the strongest candidates for further surveillance and preventative treatment (5). The use of molecular approaches to elucidate the pathways involved in invasion and migration should significantly add to our understanding of AdCC pathogenesis. Using cell sublines derived from ACCS (an AdCC cell line) by in vivo selection in mice, Ishii et al. (6) demonstrated that interactions between β-catenin and E-cadherin are associated with cell adhesion and lead to tumor metastasis. Further analysis of the molecular mechanisms involved in AdCC should contribute to the identification of potential therapeutic targets.β-catenin is a key molecule in Wnt signalling and plays an important role in cell growth, development, and cancer. The phosphorylation of β-catenin is regulated by several kinases and phosphatases (7). In the absence of extracellular activation, phosphorylated β-catenin is degraded by proteasomes in the cytoplasm. Upon activation of the Wnt signalling pathway, these proteasomes are inhibited, and 53 This article is freely accessible online.

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“…The protein kinase B/Akt signaling pathway plays essential roles in tumor growth, transformation, cell survival, and induced apoptosis and mediates drug sensitivity (Chakraborty et al, 2010;Liu et al, 2010;Tan et al, 2010;Ou et al, 2011). Findings indicate that PDK1 regulates vascular remodeling and promotes EMT in cardiac development (Feng et al, 2010) and that physical association of PDK1 with AKT1 is sufficient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase (Ding et al, 2010).…”

Section: Protein Kinase Bmentioning

confidence: 98%

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

et al. 2012

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B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer

Cited by 101 publications

References 53 publications

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

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