Expression of the B56δ subunit of protein phosphatase 2A and &lt;i&gt;Mea1&lt;/i&gt; in mouse spermatogenesis. Identification of a new B56γ subunit (B56γ4) specifically expressed in testis

Kierszenbaum, Abraham L.; Rivkin, Eugene; Tres, Laura L.; Duan, Chaojun; Goldberg, Ellen H.; Szot, Maria; Grigoriev, Vitalii G.; Mahadevaiah, Shantha K.; Ojarikre, Obah A.; Touré, Aminata; Glasenapp, E. von; Rattigan, Áine; Turner, Jonathan M.; Elliott, David J.; Burgoyne, Paul S.

doi:10.1159/000076823

Cited by 8 publications

(2 citation statements)

References 48 publications

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“…Amino acids of the spliced variants are identical until exon 12, and B56γ2, γ3, and γ4 have an additional exon or exons [72], [73]. In regard to a specific binding domain, they all have the same amino acids from 391 to 402, which constitute a domain required for interaction with p53 [49].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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Extracellular signal-regulated kinase (ERK) signalling plays a central role in various biological processes, including cell migration, but it remains unknown what factors directly regulate the strength and duration of ERK activation. We found that, among the B56 family of protein phosphatase 2A (PP2A) regulatory subunits, B56γ1 suppressed EGF-induced cell migration on collagen, bound to phosphorylated-ERK, and dephosphorylated ERK, whereas B56α1 and B56β1 did not. B56γ1 was immunolocalized in nuclei. The IER3 protein was immediately highly expressed in response to costimulation of cells with EGF and collagen. Knockdown of IER3 inhibited cell migration and enhanced dephosphorylation of ERK. Analysis of the time course of PP2A-B56γ1 activity following the costimulation showed an immediate loss of phosphatase activity, followed by a rapid increase in activity, and this activity then remained at a stable level that was lower than the original level. Our results indicate that the strength and duration of the nuclear ERK activation signal that is initially induced by ERK kinase (MEK) are determined at least in part by modulation of the phosphatase activity of PP2A-B56γ1 through two independent pathways.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…Interestingly, although the mutations are spread across the entire B56γ sequence, they cluster more frequently toward the center of the gene, notably on the HEAT-repeat 4, 5, 6 and in a very small domain (aa 383–410) that contains the p53-binding domain (Figure 1), suggesting there are potential cancer mutation hot spots in the gene. The human B56γ transcript has at least three long splice variants known as γ1, γ2, and γ3 (15, 16) and most of the mutations we identified are common to all three variants. To begin investigating their function in tumor suppression, we used site directed mutagenesis to generate eleven of the new mutations (A61V, E164K, A212T, S220N, S251R, Q256R, L257R, E266R, P274T, H287Q, and P289S; Figure 1).…”

Section: Resultsmentioning

confidence: 96%

B56γ Tumor-Associated Mutations Provide New Mechanisms for B56γ-PP2A Tumor Suppressor Activity

Nobumori

Shouse

et al. 2013

Molecular Cancer Research

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A subset of the hetero-trimeric PP2A serine/threonine phosphatases that contain B56, and in particular B56γ, can function as tumor suppressors. In response to DNA damage, the B56γ subunit complexes with the PP2A AC core (B56γ–PP2A) and binds p53. This event promotes PP2A-mediated dephosphorylation of p53 at Thr55, which induces expression of p21, and the subsequent inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ–PP2A also inhibits cell proliferation and transformation by a second, as yet unknown, p53-independent mechanism. Here, we characterized a panel of B56γ mutations found in human cancer samples and cancer cell lines and showed that the mutations lost B56γ tumor-suppressive activity by two distinct mechanisms; one is by disrupting interaction with the PP2A AC core and the other with B56γ–PP2A substrates (p53 and unknown proteins). For the first mechanism, due to the absence of the C catalytic subunit in the complex, the mutants would be unable to mediate dephosphorylation of any substrate and thus failed to promote both p53-dependent and p53–independent tumor-suppressive function of B56γ-PP2A. For the second mechanism, the mutants lacked specific substrate interactions and thus partially lost tumor-suppressive function, i.e. either p53-dependent or p53-independent contingent upon which substrate binding was affected. Overall the data provide new insight into the mechanisms for inactivation of tumor-suppressive function of B56γ and further indicate the importance of B56γ-PP2A in tumorigenesis.

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ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ–PP2A

et al. 2011

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Protein phosphatase 2A (PP2A) is a family of heterotrimeric protein phosphatases that has a multitude of functions inside the cell, acting through various substrate targets in cell-signaling pathways. Recent evidence suggests that a subset of PP2A holoenzymes function as tumor suppressors and one particular family of B subunits, B56, are implicated in this function. However, the regulatory mechanisms that govern activation of B56-PP2A tumor-suppressive function have not been elucidated. In the present study, we demonstrate that ataxiatelangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56c3, B56c2 and B56d, after DNA damage. We further show that phosphorylation of B56c3 at Ser510 leads to an increase in B56c3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. In addition, we found that under cell growth conditions B56c3 is kept at low levels through the actions of the E3 ubiquitin ligase MDM2, and, importantly, phosphorylation of B56c3 by ATM leads to upregulation of the protein by blocking MDM2-mediated B56c3 ubiquitination. Finally, we show that Ser510 phosphorylation significantly enhances the ability of B56c3 to inhibit cell proliferation and anchorage-independent growth. These results provide mechanistic insight into the regulation of PP2A tumor-suppressive function, and suggest a model for parallel regulation of p53 and B56c3.

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Expression of the B56δ subunit of protein phosphatase 2A and <i>Mea1</i> in mouse spermatogenesis. Identification of a new B56γ subunit (B56γ4) specifically expressed in testis

Cited by 8 publications

References 48 publications

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

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

B56γ Tumor-Associated Mutations Provide New Mechanisms for B56γ-PP2A Tumor Suppressor Activity

ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ–PP2A

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